3-108162482-A-C

Position:

• chr3-108162482-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018010.4(IFT57):​c.1285T>G​(p.Tyr429Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFT57 NM_018010.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

Genes affected

IFT57 (HGNC:17367): (intraflagellar transport 57) Predicted to enable DNA binding activity. Acts upstream of or within activation of cysteine-type endopeptidase activity involved in apoptotic process; apoptotic process; and regulation of apoptotic process. Predicted to be located in ciliary basal body. Predicted to be part of axoneme and intraciliary transport particle B. Predicted to be active in Golgi apparatus; centrosome; and cilium. Implicated in orofaciodigital syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFT57	NM_018010.4	c.1285T>G	p.Tyr429Asp	missense_variant	11/11	ENST00000264538.4	NP_060480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFT57	ENST00000264538.4	c.1285T>G	p.Tyr429Asp	missense_variant	11/11	1	NM_018010.4	ENSP00000264538	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with IFT57-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 429 of the IFT57 protein (p.Tyr429Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
Polyphen		0.93	P
Vest4		0.72
MutPred		0.44		Loss of helix (P = 0.0376);
MVP		0.75
MPC		0.97
ClinPred		0.86	D
GERP RS		5.9
Varity_R		0.23
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-107881329;