rs111753827

Positions:

• chr5-90672657-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032119.4(ADGRV1):​c.4864T>C​(p.Tyr1622His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000713 in 1,613,690 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (7 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.44

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006860465).
• BP6: Variant 5-90672657-T-C is Benign according to our data. Variant chr5-90672657-T-C is described in ClinVar as [Benign]. Clinvar id is 226648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90672657-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00356 (543/152342) while in subpopulation AFR AF= 0.0118 (489/41588). AF 95% confidence interval is 0.0109. There are 2 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.4864T>C	p.Tyr1622His	missense_variant	22/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.4864T>C	p.Tyr1622His	missense_variant	22/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.000943 AC: 235 AN: 249098 Hom.: 1 AF XY: 0.000725 AC XY: 98 AN XY: 135144

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000416 AC: 608 AN: 1461348 Hom.: 7 Cov.: 31 AF XY: 0.000349 AC XY: 254 AN XY: 726970

Gnomad4 AFR exome AF: 0.0127

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00356 AC: 543 AN: 152342 Hom.: 2 Cov.: 32 AF XY: 0.00364 AC XY: 271 AN XY: 74496

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000634 Hom.: 0

Bravo AF: 0.00408

ESP6500AA AF: 0.0119 AC: 45

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.00108 AC: 131

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Tyr1622His in Exon 22 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 1.2% (38/3086) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs111753827). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	.;T;T
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.86	N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	.;N;.
REVEL	Benign	0.11
Sift	Benign	0.21	.;T;.
Sift4G	Benign	0.099	.;T;.
Polyphen		1.0	D;D;.
Vest4		0.71
MVP		0.50
MPC		0.36
ClinPred		0.022	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.41

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: rs111753827; hg19: chr5-89968474;