10-71751727-G-A

Position:

chr10-71751727-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_022153.2(VSIR):c.839C>T(p.Ser280Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,585,754 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0049 ( 25 hom. )

Consequence

VSIR
NM_022153.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 8.58

Variant links:

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]

VSIR links:

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]

CDH23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039882004).

BP6

Variant 10-71751727-G-A is Benign according to our data. Variant chr10-71751727-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1684840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VSIR	NM_022153.2 linkuse as main transcript	c.839C>T	p.Ser280Leu	missense_variant	6/7	ENST00000394957.8	NP_071436.1
CDH23	NM_022124.6 linkuse as main transcript	c.4845+9806G>A		intron_variant		ENST00000224721.12	NP_071407.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VSIR	ENST00000394957.8 linkuse as main transcript	c.839C>T	p.Ser280Leu	missense_variant	6/7	1	NM_022153.2	ENSP00000378409	P1
CDH23	ENST00000224721.12 linkuse as main transcript	c.4845+9806G>A		intron_variant		5	NM_022124.6	ENSP00000224721	P1	Q9H251-1
VSIR	ENST00000470317.2 linkuse as main transcript	n.324C>T		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes

AF:

0.00364

AC:

554

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00606

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00332

AC:

754

AN:

227124

Hom.:

AF XY:

0.00327

AC XY:

402

AN XY:

123088

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.00161

Gnomad ASJ exome

AF:

0.00223

Gnomad EAS exome

AF:

0.0000586

Gnomad SAS exome

AF:

0.000186

Gnomad FIN exome

AF:

0.00190

Gnomad NFE exome

AF:

0.00587

Gnomad OTH exome

AF:

0.00295

GnomAD4 exome

AF:

0.00494

AC:

7087

AN:

1433432

Hom.:

Cov.:

AF XY:

0.00477

AC XY:

3392

AN XY:

711778

show subpopulations

Gnomad4 AFR exome

AF:

0.000869

Gnomad4 AMR exome

AF:

0.00164

Gnomad4 ASJ exome

AF:

0.00262

Gnomad4 EAS exome

AF:

0.0000508

Gnomad4 SAS exome

AF:

0.000169

Gnomad4 FIN exome

AF:

0.00184

Gnomad4 NFE exome

AF:

0.00601

Gnomad4 OTH exome

AF:

0.00345

GnomAD4 genome

AF:

0.00363

AC:

553

AN:

152322

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

253

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.00606

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00537

Hom.:

Bravo

AF:

0.00339

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00334

AC:

405

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CDH23: BS2; VSIR: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Autosomal recessive nonsyndromic hearing loss 12;C1832845:Usher syndrome type 1D;C4539685:Pituitary adenoma 5, multiple types

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.049

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.38

MutationTaster

Benign

1.0

D;D

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MVP

0.68

MPC

0.86

ClinPred

0.038

GERP RS

6.1

Varity_R

0.79

gMVP

0.23

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over