rs267607193

chr3-129440351-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_052989.3(IFT122):c.21G>C(p.Trp7Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT122 NM_052989.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.07

Genes affected

IFT122 (HGNC:13556): (intraflagellar transport 122) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This cytoplasmic protein contains seven WD repeats and an AF-2 domain which function by recruiting coregulatory molecules and in transcriptional activation. Mutations in this gene cause cranioectodermal dysplasia-1. A related pseudogene is located on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-129440351-G-C is Pathogenic according to our data. Variant chr3-129440351-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4638.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT122	NM_052989.3	c.21G>C	p.Trp7Cys	missense_variant	1/30	ENST00000348417.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT122	ENST00000348417.7	c.21G>C	p.Trp7Cys	missense_variant	1/30	1	NM_052989.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Cranioectodermal dysplasia 1 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 11, 2010	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Uncertain	0.0087	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-9.1	D;D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;D
Vest4		0.63
MutPred		0.61		Loss of catalytic residue at L5 (P = 0.004);Loss of catalytic residue at L5 (P = 0.004);Loss of catalytic residue at L5 (P = 0.004);Loss of catalytic residue at L5 (P = 0.004);Loss of catalytic residue at L5 (P = 0.004);Loss of catalytic residue at L5 (P = 0.004);
MVP		0.90
MPC		1.0
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.77

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: rs267607193; hg19: chr3-129159194;