10-71762023-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_022153.2(VSIR):c.86C>T(p.Pro29Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,596,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: VSIR NM_022153.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.283

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0133601725).
• BP6: Variant 10-71762023-G-A is Benign according to our data. Variant chr10-71762023-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3189140.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSIR	NM_022153.2	c.86C>T	p.Pro29Leu	missense_variant	2/7	ENST00000394957.8
CDH23	NM_022124.6	c.4846-15657G>A		intron_variant		ENST00000224721.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSIR	ENST00000394957.8	c.86C>T	p.Pro29Leu	missense_variant	2/7	1	NM_022153.2	P1
CDH23	ENST00000224721.12	c.4846-15657G>A		intron_variant		5	NM_022124.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000124 AC: 29 AN: 234448 Hom.: 0 AF XY: 0.0000632 AC XY: 8 AN XY: 126626

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.000352

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000509

Gnomad NFE exome AF: 0.0000571

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.0000485 AC: 70 AN: 1443754 Hom.: 0 Cov.: 34 AF XY: 0.0000391 AC XY: 28 AN XY: 716056

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.000523

Gnomad4 ASJ exome AF: 0.000442

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000156

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74468

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000879 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	15
Dann	Benign	0.93
DEOGEN2	Benign	0.000030	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	0.12	N
REVEL	Benign	0.039
Sift	Benign	0.31	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.40		Gain of helix (P = 0.027);
MVP		0.040
MPC		0.26
ClinPred		0.037	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.033
gMVP		0.40

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: rs202090521; hg19: chr10-73521780;