chr5-90558916-A-G

Variant names:

• chr5-90558916-A-G
• NM_032119.4:c.21A>G
• ADGRV1 p.Pro7Pro

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032119.4(ADGRV1):​c.21A>G​(p.Pro7Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P7P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADGRV1 NM_032119.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9683
• Clinical Significance: Not reported in ClinVar
• 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, 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.21A>G	p.Pro7Pro	splice_region synonymous	Exon 1 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.120A>G		splice_region non_coding_transcript_exon	Exon 1 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.21A>G	p.Pro7Pro	splice_region synonymous	Exon 1 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000640281.1	TSL:1	n.80A>G		splice_region non_coding_transcript_exon	Exon 1 of 7
	ADGRV1	ENST00000508842.5	TSL:3	c.34+29401A>G		intron	N/A	ENSP00000425936.1	D6RIF0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1405934 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 694006

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 1082312

Other (OTH) AF: 0.00 AC: 0 AN: 58264

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Benign	0.69
PhyloP100		3.2
PromoterAI		-0.12	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.73
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.41		Position offset: 1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-89854733;