5-90622609-G-T

Variant names:

• chr5-90622609-G-T
• rs201180985
• NM_032119.4:c.466G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032119.4(ADGRV1):​c.466G>T​(p.Ala156Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000621 in 1,449,434 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A156T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.455
• Publications: 4 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: Orphanet, ClinGen
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08626184).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.466G>T	p.Ala156Ser	missense	Exon 5 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.565G>T		non_coding_transcript_exon	Exon 5 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.466G>T	p.Ala156Ser	missense	Exon 5 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000640281.1	TSL:1	n.525G>T		non_coding_transcript_exon	Exon 5 of 7
	ADGRV1	ENST00000508842.5	TSL:3	c.382G>T	p.Ala128Ser	missense	Exon 4 of 4	ENSP00000425936.1	D6RIF0

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000478

GnomAD4 exome AF: 0.00000617 AC: 8 AN: 1297376 Hom.: 0 Cov.: 26 AF XY: 0.00000627 AC XY: 4 AN XY: 638414

African (AFR) AF: 0.00 AC: 0 AN: 27430

American (AMR) AF: 0.00 AC: 0 AN: 25364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21286

East Asian (EAS) AF: 0.00 AC: 0 AN: 33848

South Asian (SAS) AF: 0.0000184 AC: 1 AN: 54432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 0.00000583 AC: 6 AN: 1029518

Other (OTH) AF: 0.0000189 AC: 1 AN: 53040

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74268

African (AFR) AF: 0.00 AC: 0 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.91
DANN	Benign	0.92
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.46
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.018
Sift	Benign	0.29	T
Sift4G	Benign	0.31	T
Polyphen		0.0020	B
Vest4		0.099
MutPred		0.38		Gain of disorder (P = 0.0161)
MVP		0.15
MPC		0.045
ClinPred		0.22	T
GERP RS		-1.1
Varity_R		0.052
gMVP		0.19
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs201180985; hg19: chr5-89918426;