chr5-90791344-C-G

Variant names:

• chr5-90791344-C-G
• rs79464236
• NM_032119.4:c.14515C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032119.4(ADGRV1):​c.14515C>G​(p.Gln4839Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00174 in 1,547,346 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q4839H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0022 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (51 hom.)
• Consequence: ADGRV1 NM_032119.4 missense, splice_region
• Scores: Splicing: ADA: 0.9848
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.94
• Publications: 7 publications found

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]

ADGRV1 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• febrile seizures, familial, 4

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-90791346-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438169.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008897245).
• BP6: Variant 5-90791344-C-G is Benign according to our data. Variant chr5-90791344-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0022 (335/152272) while in subpopulation EAS AF = 0.0294 (152/5170). AF 95% confidence interval is 0.0256. There are 4 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032119.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.14515C>G	p.Gln4839Glu	missense splice_region	Exon 70 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.14531C>G		splice_region non_coding_transcript_exon	Exon 70 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.14515C>G	p.Gln4839Glu	missense splice_region	Exon 70 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000638510.1	TSL:1	n.1782C>G		splice_region non_coding_transcript_exon	Exon 6 of 26
	ADGRV1	ENST00000638975.1	TSL:5	c.1144C>G	p.Gln382Glu	missense	Exon 5 of 5	ENSP00000492630.1	A0A1W2PRR5

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00324 AC: 514 AN: 158756 AF XY: 0.00313

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0226

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.000298

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00169 AC: 2362 AN: 1395074 Hom.: 51 Cov.: 30 AF XY: 0.00164 AC XY: 1127 AN XY: 687704

African (AFR) AF: 0.0000315 AC: 1 AN: 31786

American (AMR) AF: 0.00117 AC: 42 AN: 35894

Ashkenazi Jewish (ASJ) AF: 0.0000406 AC: 1 AN: 24626

East Asian (EAS) AF: 0.0381 AC: 1385 AN: 36316

South Asian (SAS) AF: 0.000716 AC: 56 AN: 78164

European-Finnish (FIN) AF: 0.0104 AC: 509 AN: 49148

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5662

European-Non Finnish (NFE) AF: 0.000256 AC: 275 AN: 1075534

Other (OTH) AF: 0.00155 AC: 90 AN: 57944

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74442

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.000915 AC: 14 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0294 AC: 152 AN: 5170

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.00134

ExAC AF: 0.00193 AC: 219

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.99	T
PhyloP100		4.9
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.69
MPC		0.084
ClinPred		0.070	T
GERP RS		5.8
PromoterAI		-0.045	Neutral
Varity_R		0.45
gMVP		0.67
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs79464236; hg19: chr5-90087161; COSMIC: COSV67997853;