chr16-1571494-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:15U:1

Conservation

PhyloP100: 6.63

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 97054.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=7, Likely_pathogenic=5}. Variant chr16-1571494-C-T is described in Lovd as [Pathogenic]. Variant chr16-1571494-C-T is described in Lovd as [Likely_pathogenic]. Variant chr16-1571494-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFT140	NM_014714.4 link	c.1565G>A	p.Gly522Glu	missense_variant	Exon 14 of 31	ENST00000426508.7	NP_055529.2	Q96RY7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFT140	ENST00000426508.7 link	c.1565G>A	p.Gly522Glu	missense_variant	Exon 14 of 31	5	NM_014714.4	ENSP00000406012.2		Q96RY7-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251382

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135858

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000267

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:15Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Saldino-Mainzer syndrome

Pathogenic:4Uncertain:1

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 -

Jan 01, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 27, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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). -

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. -

not provided

Pathogenic:3

Nov 14, 2024

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) -

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

- -

Retinitis pigmentosa 80

Pathogenic:2

Jan 05, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

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

Sep 19, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Short-rib thoracic dysplasia without polydactyly

Pathogenic:1

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.070

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

2.9

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.87

MPC

0.46

ClinPred

0.96

GERP RS

5.8

Varity_R

0.88

gMVP

0.84

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over