NM_032119.4:c.12527+6G>T

Variant names:

• chr5-90776582-G-T
• rs141701016
• NM_032119.4:c.12527+6G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_032119.4(ADGRV1):​c.12527+6G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,613,048 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: ADGRV1 NM_032119.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001513
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:11
• Conservation: PhyloP100: -0.0250
• 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-90776582-G-T is Benign according to our data. Variant chr5-90776582-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00178 (271/152150) while in subpopulation AFR AF = 0.00609 (253/41512). AF 95% confidence interval is 0.00548. There are 1 homozygotes in GnomAd4. There are 133 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.12527+6G>T		splice_region intron	N/A	NP_115495.3
	ADGRV1	NR_003149.2		n.12543+6G>T		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.12527+6G>T		splice_region intron	N/A	ENSP00000384582.2
	ADGRV1	ENST00000425867.3	TSL:5	c.1481+6G>T		splice_region intron	N/A	ENSP00000392618.3
	ADGRV1	ENST00000639431.1	TSL:5	n.265+100373G>T		intron	N/A	ENSP00000491057.1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152034 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000450 AC: 112 AN: 248946 AF XY: 0.000392

Gnomad AFR exome AF: 0.00588

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000194 AC: 284 AN: 1460898 Hom.: 1 Cov.: 31 AF XY: 0.000197 AC XY: 143 AN XY: 726752

African (AFR) AF: 0.00524 AC: 175 AN: 33422

American (AMR) AF: 0.000313 AC: 14 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000621 AC: 69 AN: 1111342

Other (OTH) AF: 0.000381 AC: 23 AN: 60306

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152150 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74370

African (AFR) AF: 0.00609 AC: 253 AN: 41512

American (AMR) AF: 0.000720 AC: 11 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67994

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000943 Hom.: 0

Bravo AF: 0.00201

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	3	not specified (4)
-	-	1	ADGRV1-related disorder (1)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.75
PhyloP100		-0.025

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0080
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: rs141701016; hg19: chr5-90072399;