5-90625211-G-A

Variant names:

• chr5-90625211-G-A
• rs876657474
• NM_032119.4:c.640G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_032119.4(ADGRV1):​c.640G>A​(p.Val214Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15
• Publications: 1 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=0.07799092).
• BP6: Variant 5-90625211-G-A is Benign according to our data. Variant chr5-90625211-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 227410.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.640G>A	p.Val214Ile	missense_variant	Exon 6 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.640G>A	p.Val214Ile	missense_variant	Exon 6 of 90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val214Ile in exon 6 of GPR98: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, 4 mammals (rat, hedgehog, elephant and aardvark) have an isoleucine (Ile) a t this position despite high nearby amino acid conservation. In addition, comput ational prediction tools do not suggest a high likelihood of impact to the prote in. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.074	T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.66	.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.38	.;N
REVEL	Benign	0.053
Sift	Benign	0.36	.;T
Sift4G	Benign	0.12	.;T
Polyphen		0.016	B;B
Vest4		0.13
MutPred		0.54		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.27
MPC		0.21
ClinPred		0.17	T
GERP RS		2.1
Varity_R		0.028
gMVP		0.26
Mutation Taster		=88/12	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: rs876657474; hg19: chr5-89921028;