NM_032119.4:c.3580G>C

Variant names:

• chr5-90652509-G-C
• rs779520200
• NM_032119.4:c.3580G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP3 BP6

The NM_032119.4(ADGRV1):​c.3580G>C​(p.Asp1194His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 9.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777
• BP6: Variant 5-90652509-G-C is Benign according to our data. Variant chr5-90652509-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505140.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.3580G>C	p.Asp1194His	missense_variant	Exon 19 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.3580G>C	p.Asp1194His	missense_variant	Exon 19 of 90	1	NM_032119.4	ENSP00000384582.2
ADGRV1	ENST00000640403.1	c.883G>C	p.Asp295His	missense_variant	Exon 9 of 29	5		ENSP00000492531.1
ADGRV1	ENST00000504142.2	n.2346G>C		non_coding_transcript_exon_variant	Exon 13 of 14	5
ADGRV1	ENST00000639676.1	n.1178G>C		non_coding_transcript_exon_variant	Exon 7 of 11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248450 Hom.: 0 AF XY: 0.0000297 AC XY: 4 AN XY: 134800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460734 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 726562

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp1194His variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome. This variant has been identified in 2/162 56 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs779520200). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogen ic role. Computational prediction tools and conservation analyses suggest that t his variant may impact the protein, though this information is not predictive en ough to determine pathogenicity. In summary, the clinical significance of the p .Asp1194His variant is uncertain. -

Usher syndrome type 2C Uncertain:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PM3 -

not provided Benign:1

Nov 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.75	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.2	.;D;.
REVEL	Uncertain	0.55
Sift	Benign	0.058	.;T;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.59		Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);.;
MVP		0.81
MPC		0.33
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.62
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs779520200; hg19: chr5-89948326;