5-91072505-T-A

Variant names:

• chr5-91072505-T-A
• rs1554214818
• NM_032119.4:c.18211T>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 rank	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.18211T>A	p.Cys6071Ser	missense_variant	Exon 86 of 90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.18211T>A	p.Cys6071Ser	missense_variant	Exon 86 of 90	1	NM_032119.4	ENSP00000384582.2

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

Oct 06, 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.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
LIST_S2	Uncertain	0.88	.;D;D;D;D;.;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.9	.;D;.;.;.;.;.
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	.;D;.;.;.;.;.
Sift4G	Uncertain	0.0060	.;D;.;.;.;.;.
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;