5-90653951-C-T

Variant names:

• chr5-90653951-C-T
• rs745380273
• NM_032119.4:c.4377C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP3 BP6 BP7

The NM_032119.4(ADGRV1):​c.4377C>T​(p.Asp1459Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,554,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.002593
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.77
• 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 -1 ACMG points.

• PP3: REVEL computational evidence supports a deleterious effect, 0.722
• BP6: Variant 5-90653951-C-T is Benign according to our data. Variant chr5-90653951-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376997.
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.

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.4377C>T	p.Asp1459Asp	splice_region synonymous	Exon 20 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.4476C>T		splice_region non_coding_transcript_exon	Exon 20 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.4377C>T	p.Asp1459Asp	splice_region synonymous	Exon 20 of 90	ENSP00000384582.2
	ADGRV1	ENST00000640403.1	TSL:5	c.1668C>T	p.Asp556Asp	splice_region synonymous	Exon 10 of 29	ENSP00000492531.1
	ADGRV1	ENST00000504142.2	TSL:5	n.3143C>T		non_coding_transcript_exon	Exon 14 of 14

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000561 AC: 9 AN: 160378 AF XY: 0.0000709

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000890

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000742 AC: 104 AN: 1401900 Hom.: 0 Cov.: 31 AF XY: 0.0000838 AC XY: 58 AN XY: 691722

African (AFR) AF: 0.0000314 AC: 1 AN: 31808

American (AMR) AF: 0.00 AC: 0 AN: 35818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 36094

South Asian (SAS) AF: 0.0000503 AC: 4 AN: 79512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.0000880 AC: 95 AN: 1080110

Other (OTH) AF: 0.0000688 AC: 4 AN: 58120

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15252

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

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

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0026
dbscSNV1_RF	Benign	0.058
SpliceAI score (max)		0.070		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: rs745380273; hg19: chr5-89949768;