10-71773420-A-G

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.20T>C(p.Leu7Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 1,603,072 control chromosomes in the GnomAD database, including 141,814 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 0.37 (10752 hom., cov: 34)
  • Exomes 𝑓: 0.42 (131062 hom.)
• Consequence: VSIR NM_022153.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.61

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=1.3959408E-4).
• BP6: Variant 10-71773420-A-G is Benign according to our data. Variant chr10-71773420-A-G is described in ClinVar as [Benign]. Clinvar id is 802587.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSIR	NM_022153.2	c.20T>C	p.Leu7Pro	missense_variant	1/7	ENST00000394957.8
CDH23	NM_022124.6	c.4846-4260A>G		intron_variant		ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSIR	ENST00000394957.8	c.20T>C	p.Leu7Pro	missense_variant	1/7	1	NM_022153.2	P1
CDH23	ENST00000224721.12	c.4846-4260A>G		intron_variant		5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55770 AN: 152106 Hom.: 10751 Cov.: 34

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.381

GnomAD3 exomes AF: 0.387 AC: 87113 AN: 224918 Hom.: 17652 AF XY: 0.403 AC XY: 49668 AN XY: 123270

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.200

Gnomad SAS exome AF: 0.500

Gnomad FIN exome AF: 0.358

Gnomad NFE exome AF: 0.436

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.420 AC: 609488 AN: 1450848 Hom.: 131062 Cov.: 49 AF XY: 0.424 AC XY: 305306 AN XY: 720838

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.276

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.496

Gnomad4 FIN exome AF: 0.364

Gnomad4 NFE exome AF: 0.435

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.366 AC: 55783 AN: 152224 Hom.: 10752 Cov.: 34 AF XY: 0.366 AC XY: 27224 AN XY: 74422

Gnomad4 AFR AF: 0.270

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.468

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.480

Gnomad4 FIN AF: 0.361

Gnomad4 NFE AF: 0.432

Gnomad4 OTH AF: 0.382

Alfa AF: 0.409 Hom.: 11044

Bravo AF: 0.355

TwinsUK AF: 0.434 AC: 1609

ALSPAC AF: 0.443 AC: 1708

ESP6500AA AF: 0.273 AC: 1188

ESP6500EA AF: 0.426 AC: 3634

ExAC AF: 0.374 AC: 44769

Asia WGS AF: 0.317 AC: 1106 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.032
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	16
Dann	Benign	0.74
DEOGEN2	Benign	0.00034	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00040	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.00014	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	2.3	N
REVEL	Benign	0.051
Sift	Benign	1.0	T
Sift4G	Benign	0.098	T
Polyphen		0.0	B
Vest4		0.062
MPC		0.41
ClinPred		0.00059	T
GERP RS		2.0
Varity_R		0.090
gMVP		0.83

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: rs3747862; hg19: chr10-73533177; COSMIC: COSV56447041;