NM_032119.4:c.14427A>C

Variant names:

• chr5-90791256-A-C
• rs727504605
• NM_032119.4:c.14427A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032119.4(ADGRV1):​c.14427A>C​(p.Glu4809Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E4809E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0800
• Publications: 0 publications found

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

ACMG classification

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=0.004512161).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.14427A>C	p.Glu4809Asp	missense_variant	Exon 70 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.14427A>C	p.Glu4809Asp	missense_variant	Exon 70 of 90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000589 AC: 143 AN: 242708 AF XY: 0.000364

Gnomad AFR exome AF: 0.00305

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000227

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.000583

Gnomad OTH exome AF: 0.00102

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000404 AC: 59 AN: 1458644 Hom.: 0 Cov.: 31 AF XY: 0.0000372 AC XY: 27 AN XY: 725282

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 85748

European-Finnish (FIN) AF: 0.000910 AC: 48 AN: 52744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110716

Other (OTH) AF: 0.0000996 AC: 6 AN: 60214

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00285 AC: 345

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T;T;.;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.82
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.59	.;T;T;T;T
MetaRNN	Benign	0.0045	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		0.080
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.54	.;N;.;.;.
REVEL	Benign	0.0070
Sift	Benign	0.13	.;T;.;.;.
Sift4G	Benign	0.20	.;T;.;.;.
Polyphen		0.0030	B;B;.;.;.
Vest4		0.19
MutPred		0.24		Loss of methylation at K4808 (P = 0.1033);Loss of methylation at K4808 (P = 0.1033);.;.;.;
MVP		0.20
MPC		0.046
ClinPred		0.0045	T
GERP RS		-0.78
PromoterAI		0.019	Neutral
Varity_R		0.032
gMVP		0.36
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs727504605; hg19: chr5-90087073; COSMIC: COSV67980018;