NM_032119.4:c.12269C>A

Variant names:

• chr5-90763453-C-A
• rs199839743
• NM_032119.4:c.12269C>A

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.12269C>A​(p.Thr4090Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,612,340 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T4090T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (28 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.03
• Publications: 14 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=0.016502231).
• BP6: Variant 5-90763453-C-A is Benign according to our data. Variant chr5-90763453-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46259.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 = 0.00351 (534/152188) while in subpopulation NFE AF = 0.00666 (453/68004). AF 95% confidence interval is 0.00615. There are 3 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.12269C>A	p.Thr4090Asn	missense	Exon 59 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.12285C>A		non_coding_transcript_exon	Exon 59 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.12269C>A	p.Thr4090Asn	missense	Exon 59 of 90	ENSP00000384582.2
	ADGRV1	ENST00000425867.3	TSL:5	c.1223C>A	p.Thr408Asn	missense	Exon 7 of 38	ENSP00000392618.3
	ADGRV1	ENST00000640464.1	TSL:5	n.2688C>A		non_coding_transcript_exon	Exon 16 of 21

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 534 AN: 152070 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00287 AC: 714 AN: 249016 AF XY: 0.00295

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00572 AC: 8348 AN: 1460152 Hom.: 28 Cov.: 32 AF XY: 0.00554 AC XY: 4020 AN XY: 726116

African (AFR) AF: 0.000717 AC: 24 AN: 33468

American (AMR) AF: 0.000358 AC: 16 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39666

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86130

European-Finnish (FIN) AF: 0.00167 AC: 89 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00719 AC: 7983 AN: 1110614

Other (OTH) AF: 0.00368 AC: 222 AN: 60314

GnomAD4 genome AF: 0.00351 AC: 534 AN: 152188 Hom.: 3 Cov.: 32 AF XY: 0.00292 AC XY: 217 AN XY: 74414

African (AFR) AF: 0.00164 AC: 68 AN: 41522

American (AMR) AF: 0.000392 AC: 6 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.000378 AC: 4 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00666 AC: 453 AN: 68004

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00489 Hom.: 3

Bravo AF: 0.00320

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00135 AC: 5

ESP6500EA AF: 0.00561 AC: 46

ExAC AF: 0.00245 AC: 296

EpiCase AF: 0.00487

EpiControl AF: 0.00564

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	not specified (2)
-	-	1	ADGRV1-related disorder (1)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.85	T
PhyloP100		3.0
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.21
Sift	Benign	0.14	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MVP		0.68
MPC		0.32
ClinPred		0.019	T
GERP RS		4.3
Varity_R		0.38
gMVP		0.69
Mutation Taster		=63/37	disease causing (ClinVar)

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: rs199839743; hg19: chr5-90059270; COSMIC: COSV67993205; COSMIC: COSV67993205;