rs876657647
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_032119.4(ADGRV1):āc.12101T>Gā(p.Phe4034Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,300 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 Likely pathogenic (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 31)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
ADGRV1
NM_032119.4 missense
NM_032119.4 missense
Scores
5
6
2
Clinical Significance
Conservation
PhyloP100: 7.41
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.768
PP5
?
Variant 5-90759569-T-G is Pathogenic according to our data. Variant chr5-90759569-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228265.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADGRV1 | NM_032119.4 | c.12101T>G | p.Phe4034Cys | missense_variant | 58/90 | ENST00000405460.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADGRV1 | ENST00000405460.9 | c.12101T>G | p.Phe4034Cys | missense_variant | 58/90 | 1 | NM_032119.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461140Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726844
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74330
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 28, 2015 | The p.Phe4034Cys variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome and was absent from large population studi es, including >60,000 European chromosomes analyzed by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org) . Computational prediction tool s and conservation analysis suggest that this variant may impact the protein. In addition, the presence of this variant in trans with a pathogenic variant in an individual with hearing loss increases the likelihood that the p.Phe4034Cys var iant is pathogenic. In summary, although additional studies are required to full y establish its clinical significance, this variant is likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Polyphen
D;D;.
Vest4
0.94
MutPred
Loss of ubiquitination at K4039 (P = 0.1087);Loss of ubiquitination at K4039 (P = 0.1087);.;
MVP
0.71
MPC
0.37
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at