rs142356935

Variant names:

• chr5-90615022-A-G
• rs142356935
• NM_032119.4:c.207+3A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_032119.4(ADGRV1):​c.207+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000243 in 1,411,216 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: ADGRV1 NM_032119.4 splice_region, intron
• Scores: Splicing: ADA: 0.7616
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 4.67
• 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: 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 5-90615022-A-G is Benign according to our data. Variant chr5-90615022-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178353.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00112 (171/152126) while in subpopulation AFR AF = 0.00373 (155/41580). AF 95% confidence interval is 0.00325. There are 0 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.207+3A>G		splice_region intron	N/A	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.306+3A>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.207+3A>G		splice_region intron	N/A	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000640281.1	TSL:1	n.266+3A>G		splice_region intron	N/A
	ADGRV1	ENST00000508842.5	TSL:3	c.219+3A>G		splice_region intron	N/A	ENSP00000425936.1	D6RIF0

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

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: 0.0000442

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000341 AC: 32 AN: 93726 AF XY: 0.000206

Gnomad AFR exome AF: 0.00340

Gnomad AMR exome AF: 0.000340

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000947

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000137 AC: 172 AN: 1259090 Hom.: 1 Cov.: 21 AF XY: 0.000126 AC XY: 77 AN XY: 612030

African (AFR) AF: 0.00393 AC: 108 AN: 27510

American (AMR) AF: 0.000618 AC: 12 AN: 19412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19406

East Asian (EAS) AF: 0.00 AC: 0 AN: 34366

South Asian (SAS) AF: 0.00 AC: 0 AN: 54420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44650

Middle Eastern (MID) AF: 0.00103 AC: 5 AN: 4866

European-Non Finnish (NFE) AF: 0.0000249 AC: 25 AN: 1002764

Other (OTH) AF: 0.000426 AC: 22 AN: 51696

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74380

African (AFR) AF: 0.00373 AC: 155 AN: 41580

American (AMR) AF: 0.000786 AC: 12 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67888

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000749 Hom.: 1

Bravo AF: 0.00128

Asia WGS AF: 0.000289 AC: 1 AN: 3470

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.96
PhyloP100		4.7
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.0		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: rs142356935; hg19: chr5-89910839;