rs199826737

chr16-1571494-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 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:11 U:2
• Conservation: PhyloP100: 6.63

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]

ACMG classification

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: {Pathogenic=5, Uncertain_significance=2, Likely_pathogenic=4}. 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/exons	MANE	UniProt
IFT140	NM_014714.4	c.1565G>A	p.Gly522Glu	missense_variant	14/31	ENST00000426508.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT140	ENST00000426508.7	c.1565G>A	p.Gly522Glu	missense_variant	14/31	5	NM_014714.4	P1
IFT140	ENST00000439987.6	n.1626G>A		non_coding_transcript_exon_variant	13/19	2
IFT140	ENST00000565298.5	n.253G>A		non_coding_transcript_exon_variant	4/19	2
IFT140	ENST00000397417.6	c.*117G>A		3_prime_UTR_variant, NMD_transcript_variant	7/24	5

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

GnomAD3 exomes AF: 0.000127 AC: 32 AN: 251382 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135858

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.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 88 AN XY: 727120

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

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.: 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:11 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Saldino-Mainzer syndrome Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2023	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). Advanced 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 at Invitae 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. -
Pathogenic, criteria provided, single submitter	research	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	Jan 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 27, 2019	- -
Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	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). -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2022	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: 22503633, 26216056, 26766544, 32007091, 31397098, 28741273, 34890546, 23418020) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Retinitis pigmentosa 80 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 05, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Short-rib thoracic dysplasia without polydactyly Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2013

- -

IFT140-related condition Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2023

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. 2013. PubMed ID: 23418020) and in two unrelated individuals cranioectodermal dysplasia (Walczak-Sztulpa. 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. 2012. PubMed ID: 22503633). This variant is reported in 0.029% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-1621495-C-T). This variant is interpreted as likely pathogenic. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 19, 2018

- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 25, 2022

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	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
MutationTaster	Benign	1.0	D
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

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

Other links and lift over

dbSNP: rs199826737; hg19: chr16-1621495;