5-90840915-C-G

Variant names:

• chr5-90840915-C-G
• rs61748627
• NM_032119.4:c.16949C>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.16949C>G​(p.Thr5650Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,545,104 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T5650I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (4 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0990
• Publications: 2 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=0.0027784407).
• BP6: Variant 5-90840915-C-G is Benign according to our data. Variant chr5-90840915-C-G is described in ClinVar as Benign. ClinVar VariationId is 226645.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 = 0.00349 (531/152192) while in subpopulation AFR AF = 0.0123 (510/41522). AF 95% confidence interval is 0.0114. There are 5 homozygotes in GnomAd4. There are 257 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.16949C>G	p.Thr5650Ser	missense	Exon 78 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.16965C>G		non_coding_transcript_exon	Exon 78 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.16949C>G	p.Thr5650Ser	missense	Exon 78 of 90	ENSP00000384582.2
	ADGRV1	ENST00000638510.1	TSL:1	n.4216C>G		non_coding_transcript_exon	Exon 14 of 26
	ADGRV1	ENST00000425867.3	TSL:5	c.5903C>G	p.Thr1968Ser	missense	Exon 26 of 38	ENSP00000392618.3

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 515 AN: 152074 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.0000147

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00104 AC: 215 AN: 207086 AF XY: 0.000813

Gnomad AFR exome AF: 0.0132

Gnomad AMR exome AF: 0.000505

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000205

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000397 AC: 553 AN: 1392912 Hom.: 4 Cov.: 31 AF XY: 0.000368 AC XY: 252 AN XY: 685108

African (AFR) AF: 0.0145 AC: 464 AN: 31950

American (AMR) AF: 0.000596 AC: 23 AN: 38622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22256

East Asian (EAS) AF: 0.00 AC: 0 AN: 39042

South Asian (SAS) AF: 0.0000276 AC: 2 AN: 72500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50654

Middle Eastern (MID) AF: 0.000550 AC: 3 AN: 5452

European-Non Finnish (NFE) AF: 0.00000930 AC: 10 AN: 1075054

Other (OTH) AF: 0.000889 AC: 51 AN: 57382

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152192 Hom.: 5 Cov.: 32 AF XY: 0.00345 AC XY: 257 AN XY: 74400

African (AFR) AF: 0.0123 AC: 510 AN: 41522

American (AMR) AF: 0.000916 AC: 14 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.00414

ESP6500AA AF: 0.0117 AC: 47

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00106 AC: 128

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.0
DANN	Benign	0.26
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.099
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.017
Sift	Benign	0.83	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.070
MutPred		0.37		Gain of disorder (P = 0.0852)
MVP		0.081
MPC		0.045
ClinPred		0.0010	T
GERP RS		-6.1
Varity_R		0.015
gMVP		0.13
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: rs61748627; hg19: chr5-90136732;