chr3-108162535-T-C

Position:

• chr3-108162535-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018010.4(IFT57):​c.1232A>G​(p.Asn411Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,612,394 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (10 hom., cov: 32)
  • Exomes 𝑓: 0.012 (128 hom.)
• Consequence: IFT57 NM_018010.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.39

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008654356).
• BP6: Variant 3-108162535-T-C is Benign according to our data. Variant chr3-108162535-T-C is described in ClinVar as [Benign]. Clinvar id is 774602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0122 (17837/1460060) while in subpopulation MID AF= 0.029 (167/5760). AF 95% confidence interval is 0.0254. There are 128 homozygotes in gnomad4_exome. There are 8935 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFT57	NM_018010.4	c.1232A>G	p.Asn411Ser	missense_variant	11/11	ENST00000264538.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFT57	ENST00000264538.4	c.1232A>G	p.Asn411Ser	missense_variant	11/11	1	NM_018010.4	P1

Frequencies

GnomAD3 genomes AF: 0.00897 AC: 1366 AN: 152216 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0101 AC: 2533 AN: 250672 Hom.: 17 AF XY: 0.0108 AC XY: 1461 AN XY: 135500

Gnomad AFR exome AF: 0.00167

Gnomad AMR exome AF: 0.00930

Gnomad ASJ exome AF: 0.00814

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00845

Gnomad FIN exome AF: 0.00883

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0122 AC: 17837 AN: 1460060 Hom.: 128 Cov.: 30 AF XY: 0.0123 AC XY: 8935 AN XY: 726330

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00909

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00887

Gnomad4 FIN exome AF: 0.00819

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00895 AC: 1364 AN: 152334 Hom.: 10 Cov.: 32 AF XY: 0.00843 AC XY: 628 AN XY: 74492

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.00555

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0125 Hom.: 20

Bravo AF: 0.00937

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0143 AC: 123

ExAC AF: 0.00981 AC: 1191

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IFT57-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.24
Sift	Benign	0.087	T
Sift4G	Benign	0.35	T
Polyphen		0.94	P
Vest4		0.66
MPC		0.20
ClinPred		0.064	T
GERP RS		5.9
Varity_R		0.14
gMVP		0.068

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: rs35713185; hg19: chr3-107881382; COSMIC: COSV52709683; COSMIC: COSV52709683;