rs727504831

Variant names:

• chr5-90558916-A-C
• rs727504831
• NM_032119.4:c.21A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_032119.4(ADGRV1):​c.21A>C​(p.Pro7Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000963 in 1,557,966 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9392
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.23
• Publications: 0 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 5-90558916-A-C is Benign according to our data. Variant chr5-90558916-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179382.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.21A>C	p.Pro7Pro	splice_region synonymous	Exon 1 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.120A>C		splice_region non_coding_transcript_exon	Exon 1 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.21A>C	p.Pro7Pro	splice_region synonymous	Exon 1 of 90	ENSP00000384582.2
	ADGRV1	ENST00000640281.1	TSL:1	n.80A>C		splice_region non_coding_transcript_exon	Exon 1 of 7
	ADGRV1	ENST00000508842.5	TSL:3	c.34+29401A>C		intron	N/A	ENSP00000425936.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

GnomAD2 exomes AF: 0.00000618 AC: 1 AN: 161940 AF XY: 0.0000116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000854 AC: 12 AN: 1405934 Hom.: 0 Cov.: 30 AF XY: 0.0000101 AC XY: 7 AN XY: 694006

African (AFR) AF: 0.00 AC: 0 AN: 32268

American (AMR) AF: 0.0000827 AC: 3 AN: 36284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25192

East Asian (EAS) AF: 0.00 AC: 0 AN: 36748

South Asian (SAS) AF: 0.00 AC: 0 AN: 79922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5538

European-Non Finnish (NFE) AF: 0.00000739 AC: 8 AN: 1082312

Other (OTH) AF: 0.0000172 AC: 1 AN: 58264

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.000196 AC: 3 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.69
PhyloP100		3.2
PromoterAI		-0.089	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: 1

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

Other links and lift over

dbSNP: rs727504831; hg19: chr5-89854733;