chr5-90779087-C-T

Variant names:

• chr5-90779087-C-T
• rs1554113480
• NM_032119.4:c.13072C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032119.4(ADGRV1):​c.13072C>T​(p.Leu4358Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30061507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.13072C>T	p.Leu4358Phe	missense_variant	Exon 64 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.13072C>T	p.Leu4358Phe	missense_variant	Exon 64 of 90	1	NM_032119.4	ENSP00000384582.2
ADGRV1	ENST00000425867.3	c.2026C>T	p.Leu676Phe	missense_variant	Exon 12 of 38	5		ENSP00000392618.3
ADGRV1	ENST00000640464.1	n.3491C>T		non_coding_transcript_exon_variant	Exon 21 of 21	5
ADGRV1	ENST00000639431.1	n.265+102878C>T		intron_variant	Intron 2 of 4	5		ENSP00000491057.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 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.Leu4358Phe variant in GPR98 has not been previously reported in individual s with hearing loss and was absent from large population studies. Computational prediction tools and conservation analyses suggest that the p.Leu4358Phe variant may impact the protein, though this information is not predictive enough to det ermine pathogenicity. In summary, the clinical significance of the p.Leu4358Phe variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	.;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	.;D;.
REVEL	Benign	0.13
Sift	Uncertain	0.012	.;D;.
Sift4G	Uncertain	0.0090	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.70
MutPred		0.32		Loss of catalytic residue at K4355 (P = 0.1067);Loss of catalytic residue at K4355 (P = 0.1067);.;
MVP		0.73
MPC		0.28
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.49
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1554113480; hg19: chr5-90074904;