rs199826737

Variant names:

• chr16-1571494-C-T
• rs199826737
• NM_014714.4:c.1565G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_Strong PP5

The NM_014714.4(IFT140):​c.1565G>A​(p.Gly522Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000973 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: IFT140 NM_014714.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:1
• Conservation: PhyloP100: 6.63
• Publications: 11 publications found

Genes affected

IFT140 (HGNC:29077): (intraflagellar transport 140) This gene encodes one of the subunits of the intraflagellar transport (IFT) complex A. Intraflagellar transport is involved in the genesis, resorption and signaling of primary cilia. The primary cilium is a microtubule-based sensory organelle at the surface of most quiescent mammalian cells, that receives signals from its environment, such as the flow of fluid, light or odors, and transduces those signals to the nucleus. Loss of the corresponding protein in mouse results in renal cystic disease. [provided by RefSeq, Jun 2012]

IFT140 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• IFT140-related recessive ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• short-rib thoracic dysplasia 9 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• retinitis pigmentosa 80

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941
• PP5: Variant 16-1571494-C-T is Pathogenic according to our data. Variant chr16-1571494-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97054.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014714.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT140	NM_014714.4	MANE Select	c.1565G>A	p.Gly522Glu	missense	Exon 14 of 31	NP_055529.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFT140	ENST00000426508.7	TSL:5 MANE Select	c.1565G>A	p.Gly522Glu	missense	Exon 14 of 31	ENSP00000406012.2
	IFT140	ENST00000397417.6	TSL:5	n.*117G>A		non_coding_transcript_exon	Exon 7 of 24	ENSP00000380562.2
	IFT140	ENST00000439987.6	TSL:2	n.1626G>A		non_coding_transcript_exon	Exon 13 of 19

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000127 AC: 32 AN: 251382 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000978 AC: 143 AN: 1461640 Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 88 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000111 AC: 123 AN: 1111824

Other (OTH) AF: 0.0000497 AC: 3 AN: 60382

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68044

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:16 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Saldino-Mainzer syndrome Pathogenic:5 Uncertain:1

Jan 01, 2018

Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 522 of the IFT140 protein (p.Gly522Glu). This variant is present in population databases (rs199826737, gnomAD 0.03%). This missense change has been observed in individual(s) with Jeune asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, or retinitis pigmentosa (PMID: 23418020, 26766544, 29688594). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 97054). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on IFT140 protein function. For these reasons, this variant has been classified as Pathogenic.

Feb 27, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 80 (MIM#617781), short-rib thoracic dysplasia 9 with or without polydactyly (MIM#266920) and cystic kidney disease (MONDO#0002473) (PMID: 34890546). (I) 0108 - This gene is associated with both recessive and dominant disease. Retinitis pigmentosa 80 (MIM#617781) and short-rib thoracic dysplasia 9 with or without polydactyly (MIM#266920) are inherited in an autosomal recessive manner, while cystic kidney disease (MONDO#0002473), IFT140-related is inherited in an autosomal dominant manner (OMIM, PMID: 34890546) . (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (39 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed as compound heterozygous in several individuals with syndromic skeletal dysplasia and renal abnormalities (PMIDs: 32007091, 34596737, 23418020). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Gly522Glu variant in IFT140 was identified by our study in one individual in the compound heterozygous state, with another VUS, with Short-Rib Thoracic Dysplasia with or without Polydactyly. This variant has been seen in 0.02684% (34/126700) of European (non-Finnish) chromosomes and 0.01970% (2/10150) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199826737). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant has been reported in the compound heterozygous state in four individuals (including two Serbians) with IFT140-associated diseases (PMID: 29688594). The presence of this variant in combination with reported pathogenic and likely pathogenic variants and in an individual with Short-Rib Thoracic Dysplasia with or without Polydactyly increases the likelihood that the p.Gly522Glu variant is pathogenic. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM3 (Richards 2015).

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:3

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 06, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 34758253, 22503633, 26216056, 26766544, 32007091, 31397098, 28741273, 31964843, 34890546, 29688594, Leonhard2023[FunctionalStudy], 23418020, 37734845, 37628605, 39880085, 38927725, 38927562, 39927556, 37230223, 39594267, 34596737)

Retinitis pigmentosa 80 Pathogenic:2

Jan 05, 2023

Institute of Human Genetics Munich, TUM University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Retinal dystrophy Pathogenic:2

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80 Pathogenic:1

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cranioectodermal dysplasia 5 Pathogenic:1

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

IFT140-related disorder Pathogenic:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The IFT140 c.1565G>A variant is predicted to result in the amino acid substitution p.Gly522Glu. This variant was reported in the compound heterozygous state along with a second potentially causative variant in two unrelated individuals with Jeune asphyxiating thoracic dystrophy (Schmidts et al. 2013. PubMed ID: 23418020) and in two unrelated individuals with cranioectodermal dysplasia (Walczak-Sztulpa et al. 2020. PubMed ID: 32007091). This variant was also reported in one patient with Mainzer-Saldino syndrome, although a second causative variant was not identified (Perrault et al. 2012. PubMed ID: 22503633). In addition, this variant was also reported in an individual with the autosomal dominant polycystic kidney-spectrum phenotype (Senum et al. 2021. PubMed ID: 34890546). This variant is reported in 0.029% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Of note, loss-of-function has been known to be the disease-causing mechanism for both autosomal recessive and dominant IFT140-related disorders (https://search.clinicalgenome.org/kb/genes/HGNC:29077; Senum et al. 2022. PubMed ID: 34890546). Therefore, this variant is interpreted as likely pathogenic for both autosomal recessive and dominant IFT140-related disorders.

Retinitis pigmentosa Pathogenic:1

Dec 25, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IFT140 c.1565G>A (p.Gly522Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251382 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IFT140 causing Retinitis Pigmentosa (0.00013 vs 0.00063), allowing no conclusion about variant significance. c.1565G>A has been reported in the literature as a biallelic compound heterozygous genotype in multiple comprehensively genotyped individuals affected with features of IFT140-related disorders such as Jeune asphyxiating thoracic dystrophy (JATD), inherited retinal disease (IRD) and Mainzer-Saldino syndrome (MSS) (example, Perrault_2012, Schmidts_2013, Weisschuh_2020, Geoffroy_2018, Senum_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=6; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.87
MPC		0.46
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.84
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199826737; hg19: chr16-1621495;