rs200179979

chr5-90705409-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_032119.4(ADGRV1):c.8396C>T(p.Pro2799Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,613,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.945

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-90705409-C-T is Benign according to our data. Variant chr5-90705409-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46388.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.8396C>T	p.Pro2799Leu	missense_variant	37/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.8396C>T	p.Pro2799Leu	missense_variant	37/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000173 AC: 43 AN: 248000 Hom.: 0 AF XY: 0.000186 AC XY: 25 AN XY: 134492

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000933

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000351 AC: 512 AN: 1460716 Hom.: 0 Cov.: 31 AF XY: 0.000356 AC XY: 259 AN XY: 726602

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000439

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74478

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000256 AC: 1

ESP6500EA AF: 0.000602 AC: 5

ExAC AF: 0.000207 AC: 25

EpiCase AF: 0.000328

EpiControl AF: 0.000417

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2021	Identified by exome sequencing in a patient in the published literature (Li et al., 2021) with presumed ocular histoplasmosis syndrome, but it was not reported if the patient had other variants identified that could be associated with the phenotype; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32707200) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 19, 2017

p.Pro2799Leu in exon 37 of GPR98: This variant is not expected to have clinical significance due to a lack of conservation across mammals and computational anal yses do not suggest a high likelihood of impact to the protein. It has been id entified in 21/66654 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200179979). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	12
Dann	Benign	0.93
DEOGEN2	Benign	0.28	T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
Polyphen		0.073	B;B;.
Vest4		0.15
MVP		0.39
MPC		0.065
ClinPred		0.033	T
GERP RS		4.9
Varity_R		0.12
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200179979; hg19: chr5-90001226; COSMIC: COSV67978815;