rs149544995

chr5-90840807-C-T

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.16841C>T(p.Thr5614Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000867 in 1,613,900 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (22 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.87

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=0.0068663955).
• BP6: Variant 5-90840807-C-T is Benign according to our data. Variant chr5-90840807-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000872 (1274/1461670) while in subpopulation AMR AF= 0.028 (1250/44722). AF 95% confidence interval is 0.0267. There are 22 homozygotes in gnomad4_exome. There are 514 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 19 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.16841C>T	p.Thr5614Ile	missense_variant	78/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.16841C>T	p.Thr5614Ile	missense_variant	78/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152112 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00726

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: 0.00

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00451 AC: 1123 AN: 249140 Hom.: 19 AF XY: 0.00333 AC XY: 450 AN XY: 135156

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0320

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.000872 AC: 1274 AN: 1461670 Hom.: 22 Cov.: 31 AF XY: 0.000707 AC XY: 514 AN XY: 727106

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000828 AC: 126 AN: 152230 Hom.: 1 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74426

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000190 Hom.: 1

Bravo AF: 0.00224

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.00362 AC: 437

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 31, 2017	p.Thr5614Ile in exon 78 of GPR98: This variant is not expected to have clinical significance because it has been identified in 3.7% (428/11554 ) of Latino chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs149544995). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.53
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.36	N
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
Polyphen		0.0080	B;B;.
Vest4		0.19
MVP		0.32
MPC		0.28
ClinPred		0.016	T
GERP RS		4.3
Varity_R		0.043
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs149544995; hg19: chr5-90136624;