rs56329646

Variant names:

• chr5-90716495-C-T
• rs56329646
• NM_032119.4:c.9213C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6 BP7 BS1 BS2

The NM_032119.4(ADGRV1):​c.9213C>T​(p.Asp3071Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,592,634 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (16 hom.)
• Consequence: ADGRV1 NM_032119.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.860
• Publications: 1 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: ClinGen, Orphanet
• Usher syndrome type 2C

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

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

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LOC105379077 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 5-90716495-C-T is Benign according to our data. Variant chr5-90716495-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46402.
• BP7: Synonymous conserved (PhyloP=0.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00243 (370/152192) while in subpopulation SAS AF = 0.00395 (19/4814). AF 95% confidence interval is 0.00323. There are 2 homozygotes in GnomAd4. There are 175 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.9213C>T	p.Asp3071Asp	synonymous	Exon 43 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.9229C>T		non_coding_transcript_exon	Exon 43 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.9213C>T	p.Asp3071Asp	synonymous	Exon 43 of 90	ENSP00000384582.2
	ADGRV1	ENST00000509621.1	TSL:1	n.1910C>T		non_coding_transcript_exon	Exon 11 of 26
	ADGRV1	ENST00000639473.1	TSL:5	n.4672C>T		non_coding_transcript_exon	Exon 23 of 23

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 366 AN: 152074 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00255 AC: 620 AN: 242924 AF XY: 0.00290

Gnomad AFR exome AF: 0.000716

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.00206

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00305 AC: 4392 AN: 1440442 Hom.: 16 Cov.: 30 AF XY: 0.00311 AC XY: 2219 AN XY: 714574

African (AFR) AF: 0.00103 AC: 34 AN: 33022

American (AMR) AF: 0.00198 AC: 86 AN: 43414

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 43 AN: 25468

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.00304 AC: 247 AN: 81328

European-Finnish (FIN) AF: 0.000284 AC: 15 AN: 52868

Middle Eastern (MID) AF: 0.0178 AC: 101 AN: 5676

European-Non Finnish (NFE) AF: 0.00331 AC: 3645 AN: 1099824

Other (OTH) AF: 0.00372 AC: 221 AN: 59404

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152192 Hom.: 2 Cov.: 33 AF XY: 0.00235 AC XY: 175 AN XY: 74412

African (AFR) AF: 0.000771 AC: 32 AN: 41504

American (AMR) AF: 0.00288 AC: 44 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4814

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00360 AC: 245 AN: 68004

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00275 Hom.: 0

Bravo AF: 0.00248

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	4	not specified (4)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	8.3
DANN	Benign	0.50
PhyloP100		0.86
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs56329646; hg19: chr5-90012312; COSMIC: COSV67983312; COSMIC: COSV67983312;