rs183633457

Positions:

• chr5-90810429-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The ENST00000405460.9(ADGRV1):​c.15169C>T​(p.Pro5057Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000773 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P5057P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (0 hom.)
• Consequence: ADGRV1 ENST00000405460.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 1.51

Genes affected

ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06877008).
• BP6: Variant 5-90810429-C-T is Benign according to our data. Variant chr5-90810429-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285387.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}. Variant chr5-90810429-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.15169C>T	p.Pro5057Ser	missense_variant	74/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.15169C>T	p.Pro5057Ser	missense_variant	74/90	1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000583 AC: 145 AN: 248834 Hom.: 0 AF XY: 0.000644 AC XY: 87 AN XY: 135008

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000743

Gnomad NFE exome AF: 0.000922

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000804 AC: 1175 AN: 1461530 Hom.: 0 Cov.: 32 AF XY: 0.000854 AC XY: 621 AN XY: 727028

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.000955

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74428

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000761 Hom.: 1

Bravo AF: 0.000589

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000271 AC: 1

ESP6500EA AF: 0.00134 AC: 11

ExAC AF: 0.000646 AC: 78

EpiCase AF: 0.000818

EpiControl AF: 0.000950

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jul 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 13, 2019

Variant classified as Uncertain Significance - Favor Benign. The p.Pro5057Ser variant in ADGRV1 has been previously reported in 2 individuals with hearing loss by our laboratory, including 1 who was compound heterozygous for a second variant of uncertain significance in ADGRV1. This variant has been identified in 0.09% (117/128212) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -

Optic atrophy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Usher syndrome type 2C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	.;D;.
REVEL	Benign	0.12
Sift	Benign	0.081	.;T;.
Sift4G	Uncertain	0.029	.;D;.
Polyphen		0.98	D;D;.
Vest4		0.30
MVP		0.67
MPC		0.054
ClinPred		0.051	T
GERP RS		4.7
Varity_R		0.20
gMVP		0.59

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: rs183633457; hg19: chr5-90106246;