5-90627243-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032119.4(ADGRV1):c.705A>T(p.Gln235His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000257 in 1,557,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q235Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ADGRV1
NM_032119.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.122

Publications

1 publications found

Variant links:

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]

ADGRV1 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2C
Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
febrile seizures, familial, 4
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ADGRV1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040768802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4 link	c.705A>T	p.Gln235His	missense_variant	Exon 7 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ADGRV1	ENST00000405460.9 link	c.705A>T	p.Gln235His	missense_variant	Exon 7 of 90	1	NM_032119.4	ENSP00000384582.2
ADGRV1	ENST00000640281.1 link	n.764A>T		non_coding_transcript_exon_variant	Exon 7 of 7	1
ADGRV1	ENST00000640083.1 link	n.410A>T		non_coding_transcript_exon_variant	Exon 5 of 6	5
ADGRV1	ENST00000640109.1 link	n.801A>T		non_coding_transcript_exon_variant	Exon 7 of 9	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1405490

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31414

American (AMR)

AF:

0.0000276

AC:

AN:

36180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22982

East Asian (EAS)

AF:

0.00

AC:

AN:

39124

South Asian (SAS)

AF:

0.00

AC:

AN:

75756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5470

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085276

Other (OTH)

AF:

0.00

AC:

AN:

57958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41454

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.705A>T (p.Q235H) alteration is located in exon 7 (coding exon 7) of the ADGRV1 gene. This alteration results from a A to T substitution at nucleotide position 705, causing the glutamine (Q) at amino acid position 235 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jan 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 235 of the ADGRV1 protein (p.Gln235His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ADGRV1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

5.5

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.075

T;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.56

.;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.12

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.2

.;N

REVEL

Benign

0.13

Sift

Benign

0.52

.;T

Sift4G

Benign

0.45

.;T

Polyphen

0.0010

B;B

Vest4

0.20

MutPred

0.45

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.13

MPC

0.29

ClinPred

0.087

GERP RS

-10

Varity_R

0.033

gMVP

0.53

Mutation Taster

=78/22

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over