10-71760875-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022153.2(VSIR):c.561T>G(p.Asp187Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.897 in 1,613,268 control chromosomes in the GnomAD database, including 650,292 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.90 (62219 hom., cov: 33)
  • Exomes 𝑓: 0.90 (588073 hom.)
• Consequence: VSIR NM_022153.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.655

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.452945E-7).
• BP6: Variant 10-71760875-A-C is Benign according to our data. Variant chr10-71760875-A-C is described in ClinVar as [Benign]. Clinvar id is 802586.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSIR	NM_022153.2	c.561T>G	p.Asp187Glu	missense_variant	3/7	ENST00000394957.8
CDH23	NM_022124.6	c.4846-16805A>C		intron_variant		ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSIR	ENST00000394957.8	c.561T>G	p.Asp187Glu	missense_variant	3/7	1	NM_022153.2	P1
CDH23	ENST00000224721.12	c.4846-16805A>C		intron_variant		5	NM_022124.6	P1
VSIR	ENST00000481568.2	n.397T>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137237 AN: 152094 Hom.: 62173 Cov.: 33

Gnomad AFR AF: 0.972

Gnomad AMI AF: 0.815

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.956

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.928

Gnomad FIN AF: 0.801

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.896

Gnomad OTH AF: 0.905

GnomAD3 exomes AF: 0.882 AC: 221747 AN: 251390 Hom.: 98209 AF XY: 0.887 AC XY: 120458 AN XY: 135860

Gnomad AFR exome AF: 0.972

Gnomad AMR exome AF: 0.815

Gnomad ASJ exome AF: 0.958

Gnomad EAS exome AF: 0.809

Gnomad SAS exome AF: 0.936

Gnomad FIN exome AF: 0.802

Gnomad NFE exome AF: 0.895

Gnomad OTH exome AF: 0.890

GnomAD4 exome AF: 0.897 AC: 1309851 AN: 1461056 Hom.: 588073 Cov.: 48 AF XY: 0.898 AC XY: 652643 AN XY: 726884

Gnomad4 AFR exome AF: 0.975

Gnomad4 AMR exome AF: 0.814

Gnomad4 ASJ exome AF: 0.956

Gnomad4 EAS exome AF: 0.825

Gnomad4 SAS exome AF: 0.935

Gnomad4 FIN exome AF: 0.805

Gnomad4 NFE exome AF: 0.900

Gnomad4 OTH exome AF: 0.898

GnomAD4 genome AF: 0.902 AC: 137333 AN: 152212 Hom.: 62219 Cov.: 33 AF XY: 0.898 AC XY: 66788 AN XY: 74406

Gnomad4 AFR AF: 0.972

Gnomad4 AMR AF: 0.830

Gnomad4 ASJ AF: 0.956

Gnomad4 EAS AF: 0.800

Gnomad4 SAS AF: 0.928

Gnomad4 FIN AF: 0.801

Gnomad4 NFE AF: 0.896

Gnomad4 OTH AF: 0.904

Alfa AF: 0.902 Hom.: 155030

Bravo AF: 0.906

TwinsUK AF: 0.900 AC: 3338

ALSPAC AF: 0.902 AC: 3475

ESP6500AA AF: 0.970 AC: 4272

ESP6500EA AF: 0.899 AC: 7730

ExAC AF: 0.886 AC: 107631

Asia WGS AF: 0.823 AC: 2865 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa-deafness syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	11
Dann	Benign	0.86
DEOGEN2	Benign	0.00028	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.069	T
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.8e-8	P;P
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.055
Sift	Benign	0.69	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.0030
MutPred		0.12		Gain of disorder (P = 0.1464);
MPC		0.24
ClinPred		0.00074	T
GERP RS		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.27

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: rs3747869; hg19: chr10-73520632; COSMIC: COSV56463939; COSMIC: COSV56463939;