chr5-90840983-A-G

Variant names:

• chr5-90840983-A-G
• rs41303350
• NM_032119.4:c.17017A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032119.4(ADGRV1):​c.17017A>G​(p.Lys5673Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00424 in 1,390,998 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K5673Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (17 hom.)
• Consequence: ADGRV1 NM_032119.4 missense, splice_region
• Scores: Splicing: ADA: 0.0007120
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.00
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072719157).
• BP6: Variant 5-90840983-A-G is Benign according to our data. Variant chr5-90840983-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00251 (382/152330) while in subpopulation NFE AF = 0.0041 (279/68032). AF 95% confidence interval is 0.00371. There are 1 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR,AD gene

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.17017A>G	p.Lys5673Glu	missense splice_region	Exon 78 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.17033A>G		splice_region non_coding_transcript_exon	Exon 78 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.17017A>G	p.Lys5673Glu	missense splice_region	Exon 78 of 90	ENSP00000384582.2
	ADGRV1	ENST00000638510.1	TSL:1	n.4284A>G		splice_region non_coding_transcript_exon	Exon 14 of 26
	ADGRV1	ENST00000425867.3	TSL:5	c.5971A>G	p.Lys1991Glu	missense splice_region	Exon 26 of 38	ENSP00000392618.3

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 381 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00366 AC: 541 AN: 147990 AF XY: 0.00359

Gnomad AFR exome AF: 0.000649

Gnomad AMR exome AF: 0.000653

Gnomad ASJ exome AF: 0.000684

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00242

Gnomad NFE exome AF: 0.00605

Gnomad OTH exome AF: 0.00369

GnomAD4 exome AF: 0.00445 AC: 5516 AN: 1238668 Hom.: 17 Cov.: 30 AF XY: 0.00446 AC XY: 2664 AN XY: 597042

African (AFR) AF: 0.000717 AC: 20 AN: 27900

American (AMR) AF: 0.000700 AC: 16 AN: 22844

Ashkenazi Jewish (ASJ) AF: 0.000350 AC: 6 AN: 17164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35694

South Asian (SAS) AF: 0.000437 AC: 17 AN: 38922

European-Finnish (FIN) AF: 0.00334 AC: 143 AN: 42762

Middle Eastern (MID) AF: 0.00143 AC: 7 AN: 4900

European-Non Finnish (NFE) AF: 0.00514 AC: 5132 AN: 998016

Other (OTH) AF: 0.00347 AC: 175 AN: 50466

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74486

African (AFR) AF: 0.000914 AC: 38 AN: 41572

American (AMR) AF: 0.000784 AC: 12 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00410 AC: 279 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00305 Hom.: 1

Bravo AF: 0.00260

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000803 AC: 3

ESP6500EA AF: 0.00402 AC: 33

ExAC AF: 0.00374 AC: 434

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.0082
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.0
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.75	P
Vest4		0.51
MVP		0.51
MPC		0.061
ClinPred		0.030	T
GERP RS		4.6
Varity_R		0.35
gMVP		0.59
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00071
dbscSNV1_RF	Benign	0.010
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: rs41303350; hg19: chr5-90136800;