10-71751727-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.58

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 -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 GnomAdExome at 5 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 554 AN: 152204 Hom.: 0 Cov.: 31

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.: 5 AF XY: 0.00327 AC XY: 402 AN XY: 123088

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.: 25 Cov.: 31 AF XY: 0.00477 AC XY: 3392 AN XY: 711778

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.: 0 Cov.: 31 AF XY: 0.00340 AC XY: 253 AN XY: 74474

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.: 2

Bravo AF: 0.00339

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00334 AC: 405

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

CDH23: BS2; VSIR: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	D;D
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.68
MPC		0.86
ClinPred		0.038	T
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

Other links and lift over

dbSNP: rs143240262; hg19: chr10-73511484; COSMIC: COSV99034540;