NM_032119.4:c.5851G>A

Variant names:

• chr5-90683772-G-A
• rs4916684
• NM_032119.4:c.5851G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032119.4(ADGRV1):​c.5851G>A​(p.Val1951Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,613,458 control chromosomes in the GnomAD database, including 364,981 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42168 hom., cov: 30)
  • Exomes 𝑓: 0.66 (322813 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.584
• Publications: 43 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.4812325E-7).
• BP6: Variant 5-90683772-G-A is Benign according to our data. Variant chr5-90683772-G-A is described in ClinVar as Benign. ClinVar VariationId is 46343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.5851G>A	p.Val1951Ile	missense	Exon 28 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.5950G>A		non_coding_transcript_exon	Exon 28 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.5851G>A	p.Val1951Ile	missense	Exon 28 of 90	ENSP00000384582.2
	ADGRV1	ENST00000640403.1	TSL:5	c.3142G>A	p.Val1048Ile	missense	Exon 18 of 29	ENSP00000492531.1
	ADGRV1	ENST00000639473.1	TSL:5	n.1310G>A		non_coding_transcript_exon	Exon 8 of 23

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111694 AN: 151874 Hom.: 42094 Cov.: 30

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.773

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.743

GnomAD2 exomes AF: 0.710 AC: 176347 AN: 248522 AF XY: 0.701

Gnomad AFR exome AF: 0.903

Gnomad AMR exome AF: 0.825

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.801

Gnomad FIN exome AF: 0.668

Gnomad NFE exome AF: 0.642

Gnomad OTH exome AF: 0.701

GnomAD4 exome AF: 0.662 AC: 966891 AN: 1461466 Hom.: 322813 Cov.: 55 AF XY: 0.661 AC XY: 480768 AN XY: 727024

African (AFR) AF: 0.903 AC: 30224 AN: 33476

American (AMR) AF: 0.821 AC: 36680 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 17396 AN: 26134

East Asian (EAS) AF: 0.818 AC: 32473 AN: 39690

South Asian (SAS) AF: 0.720 AC: 62085 AN: 86250

European-Finnish (FIN) AF: 0.667 AC: 35613 AN: 53376

Middle Eastern (MID) AF: 0.696 AC: 4012 AN: 5764

European-Non Finnish (NFE) AF: 0.636 AC: 706935 AN: 1111720

Other (OTH) AF: 0.687 AC: 41473 AN: 60360

GnomAD4 genome AF: 0.736 AC: 111822 AN: 151992 Hom.: 42168 Cov.: 30 AF XY: 0.738 AC XY: 54801 AN XY: 74268

African (AFR) AF: 0.897 AC: 37196 AN: 41462

American (AMR) AF: 0.773 AC: 11806 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2317 AN: 3464

East Asian (EAS) AF: 0.813 AC: 4173 AN: 5134

South Asian (SAS) AF: 0.724 AC: 3485 AN: 4812

European-Finnish (FIN) AF: 0.663 AC: 7003 AN: 10564

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.639 AC: 43453 AN: 67976

Other (OTH) AF: 0.747 AC: 1574 AN: 2108

Alfa AF: 0.677 Hom.: 144649

Bravo AF: 0.755

TwinsUK AF: 0.629 AC: 2334

ALSPAC AF: 0.649 AC: 2500

ESP6500AA AF: 0.906 AC: 3480

ESP6500EA AF: 0.645 AC: 5339

ExAC AF: 0.707 AC: 85425

Asia WGS AF: 0.808 AC: 2808 AN: 3478

EpiCase AF: 0.651

EpiControl AF: 0.649

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 2C (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.18
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.58
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.61	N
REVEL	Benign	0.053
Sift	Benign	0.77	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.042
ClinPred		0.00070	T
GERP RS		3.2
Varity_R		0.032
gMVP		0.20
Mutation Taster		=97/3	polymorphism (auto)

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: rs4916684; hg19: chr5-89979589; COSMIC: COSV67980016;