chr5-90720961-C-T

Variant names:

• chr5-90720961-C-T
• rs114137750
• NM_032119.4:c.9650C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032119.4(ADGRV1):​c.9650C>T​(p.Ala3217Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,610,820 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A3217A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (13 hom., cov: 32)
  • Exomes 𝑓: 0.011 (113 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 3.51
• Publications: 15 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: Orphanet, ClinGen
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• febrile seizures, familial, 4

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LOC105379077 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056247115).
• BP6: Variant 5-90720961-C-T is Benign according to our data. Variant chr5-90720961-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158655.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00819 (1247/152178) while in subpopulation NFE AF = 0.0117 (798/68004). AF 95% confidence interval is 0.0111. There are 13 homozygotes in GnomAd4. There are 603 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.9650C>T	p.Ala3217Val	missense	Exon 45 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.9666C>T		non_coding_transcript_exon	Exon 45 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.9650C>T	p.Ala3217Val	missense	Exon 45 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000509621.1	TSL:1	n.2347C>T		non_coding_transcript_exon	Exon 13 of 26
	ADGRV1	ENST00000640374.1	TSL:5	n.2794C>T		non_coding_transcript_exon	Exon 15 of 27

Frequencies

GnomAD3 genomes AF: 0.00820 AC: 1247 AN: 152060 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.00528

GnomAD2 exomes AF: 0.00897 AC: 2230 AN: 248662 AF XY: 0.00894

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.00355

Gnomad ASJ exome AF: 0.00617

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0109 AC: 15912 AN: 1458642 Hom.: 113 Cov.: 29 AF XY: 0.0107 AC XY: 7763 AN XY: 725708

African (AFR) AF: 0.00174 AC: 58 AN: 33374

American (AMR) AF: 0.00363 AC: 162 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00726 AC: 189 AN: 26034

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39544

South Asian (SAS) AF: 0.00266 AC: 229 AN: 85984

European-Finnish (FIN) AF: 0.0198 AC: 1052 AN: 53182

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5754

European-Non Finnish (NFE) AF: 0.0123 AC: 13675 AN: 1109950

Other (OTH) AF: 0.00880 AC: 530 AN: 60214

GnomAD4 genome AF: 0.00819 AC: 1247 AN: 152178 Hom.: 13 Cov.: 32 AF XY: 0.00810 AC XY: 603 AN XY: 74400

African (AFR) AF: 0.00236 AC: 98 AN: 41524

American (AMR) AF: 0.00471 AC: 72 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4824

European-Finnish (FIN) AF: 0.0215 AC: 228 AN: 10588

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0117 AC: 798 AN: 68004

Other (OTH) AF: 0.00522 AC: 11 AN: 2106

Alfa AF: 0.0100 Hom.: 16

Bravo AF: 0.00671

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00237 AC: 9

ESP6500EA AF: 0.0102 AC: 84

ExAC AF: 0.00953 AC: 1152

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	2	Usher syndrome type 2C (2)
-	1	-	Febrile seizures, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.90	T
PhyloP100		3.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.079
Sift	Benign	0.043	D
Sift4G	Uncertain	0.044	D
Polyphen		0.068	B
Vest4		0.26
MVP		0.61
MPC		0.074
ClinPred		0.013	T
GERP RS		5.8
Varity_R		0.11
gMVP		0.41
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs114137750; hg19: chr5-90016778; COSMIC: COSV108245832; COSMIC: COSV108245832;