rs1554214818

Positions:

• chr5-91072505-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032119.4(ADGRV1):​c.18211T>A​(p.Cys6071Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.57

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]

LUCAT1 (HGNC:48498): (lung cancer associated transcript 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.18211T>A	p.Cys6071Ser	missense_variant	86/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.18211T>A	p.Cys6071Ser	missense_variant	86/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 06, 2016

The p.Cys6071Ser variant in GPR98 has not been previously reported in individual s with Usher syndrome and was absent from large population studies. Computationa l prediction tools and conservation analyses suggest that this variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. In summary, the clinical significance of the p.Cys6071Ser variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
Polyphen		1.0	D;D;.;.;.;.;.
Vest4		0.79
MutPred		0.52		Loss of catalytic residue at L6072 (P = 0.0138);Loss of catalytic residue at L6072 (P = 0.0138);.;.;.;.;.;
MVP		0.74
MPC		0.29
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.77
gMVP		0.76

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: rs1554214818; hg19: chr5-90368322;