10-71752985-G-A

Position:

• chr10-71752985-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_022153.2(VSIR):​c.694C>T​(p.Arg232Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,612,692 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: VSIR NM_022153.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

Genes affected

VSIR (HGNC:30085): (V-set immunoregulatory receptor) Enables endopeptidase activator activity; enzyme binding activity; and identical protein binding activity. Involved in several processes, including negative regulation of cytokine production; positive regulation of macromolecule metabolic process; and regulation of T cell activation. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CDH23 (HGNC:13733): (cadherin related 23) This gene is a member of the cadherin superfamily, whose genes encode calcium dependent cell-cell adhesion glycoproteins. The encoded protein is thought to be involved in stereocilia organization and hair bundle formation. The gene is located in a region containing the human deafness loci DFNB12 and USH1D. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of this cadherin-like gene. Upregulation of this gene may also be associated with breast cancer. Alternative splice variants encoding different isoforms have been described. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VSIR	NM_022153.2	c.694C>T	p.Arg232Trp	missense_variant	5/7	ENST00000394957.8	NP_071436.1
CDH23	NM_022124.6	c.4845+11064G>A		intron_variant		ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VSIR	ENST00000394957.8	c.694C>T	p.Arg232Trp	missense_variant	5/7	1	NM_022153.2	ENSP00000378409	P1
CDH23	ENST00000224721.12	c.4845+11064G>A		intron_variant		5	NM_022124.6	ENSP00000224721	P1
VSIR	ENST00000470317.2	n.179C>T		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000278 AC: 69 AN: 248488 Hom.: 0 AF XY: 0.000372 AC XY: 50 AN XY: 134416

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.000959

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000207 AC: 302 AN: 1460394 Hom.: 2 Cov.: 30 AF XY: 0.000255 AC XY: 185 AN XY: 726400

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.0000939

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000239 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000296 AC: 36

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 07, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	0.0064	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.76
MPC		0.57
ClinPred		0.16	T
GERP RS		3.8
Varity_R		0.63
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143020453; hg19: chr10-73512742;