NM_001083909.3:c.497C>T

Variant names:

• chr10-133127328-C-T
• rs1852395994
• NM_001083909.3:c.497C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001083909.3(ADGRA1):​c.497C>T​(p.Ala166Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADGRA1 NM_001083909.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59
• Publications: 0 publications found

Genes affected

ADGRA1 (HGNC:13838): (adhesion G protein-coupled receptor A1) This gene encodes a protein that belongs to the adhesion family of G-protein-coupled receptors. Members of this family function in several sensory systems and regulate blood pressure, immune responses, food intake and development. A similar protein in rodents is thought to play a role in in the regulation of neuronal signaling pathways. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Mar 2014]

ENSG00000297384 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37379873).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083909.3. 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
	ADGRA1	NM_001083909.3	MANE Select	c.497C>T	p.Ala166Val	missense	Exon 6 of 7	NP_001077378.1	Q86SQ6-3
	ADGRA1	NM_001291085.2		c.206C>T	p.Ala69Val	missense	Exon 3 of 4	NP_001278014.1	Q86SQ6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRA1	ENST00000392607.8	TSL:5 MANE Select	c.497C>T	p.Ala166Val	missense	Exon 6 of 7	ENSP00000376384.3	Q86SQ6-3
	ADGRA1	ENST00000392606.2	TSL:1	c.206C>T	p.Ala69Val	missense	Exon 3 of 4	ENSP00000376383.2	Q86SQ6-2
	ADGRA1	ENST00000864054.1		c.497C>T	p.Ala166Val	missense	Exon 5 of 6	ENSP00000534113.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.95e-7 AC: 1 AN: 1439372 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 715538

African (AFR) AF: 0.00 AC: 0 AN: 32040

American (AMR) AF: 0.0000240 AC: 1 AN: 41656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25676

East Asian (EAS) AF: 0.00 AC: 0 AN: 37672

South Asian (SAS) AF: 0.00 AC: 0 AN: 82688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101848

Other (OTH) AF: 0.00 AC: 0 AN: 59522

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.89	T
PhyloP100		5.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.14
Sift	Benign	0.030	D
Sift4G	Benign	0.30	T
Polyphen		0.95	P
Vest4		0.33
MutPred		0.53		Gain of catalytic residue at A166 (P = 0.0634)
MVP		0.21
MPC		0.72
ClinPred		0.69	D
GERP RS		3.6
Varity_R		0.11
gMVP		0.34
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1852395994; hg19: chr10-134940832; COSMIC: COSV66925242;