10-133128432-C-T

Variant names:

• chr10-133128432-C-T
• rs369109023
• NM_001083909.3:c.604C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001083909.3(ADGRA1):​c.604C>T​(p.Arg202Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,605,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ADGRA1 NM_001083909.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.604C>T	p.Arg202Trp	missense	Exon 7 of 7	NP_001077378.1	Q86SQ6-3
	ADGRA1	NM_001291085.2		c.313C>T	p.Arg105Trp	missense	Exon 4 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.604C>T	p.Arg202Trp	missense	Exon 7 of 7	ENSP00000376384.3	Q86SQ6-3
	ADGRA1	ENST00000392606.2	TSL:1	c.313C>T	p.Arg105Trp	missense	Exon 4 of 4	ENSP00000376383.2	Q86SQ6-2
	ADGRA1	ENST00000864054.1		c.604C>T	p.Arg202Trp	missense	Exon 6 of 6	ENSP00000534113.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152186 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000311 AC: 7 AN: 224850 AF XY: 0.0000322

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000901

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000205

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000895 AC: 13 AN: 1452944 Hom.: 0 Cov.: 30 AF XY: 0.00000831 AC XY: 6 AN XY: 722282

African (AFR) AF: 0.00 AC: 0 AN: 33008

American (AMR) AF: 0.0000453 AC: 2 AN: 44110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.0000766 AC: 3 AN: 39158

South Asian (SAS) AF: 0.00 AC: 0 AN: 84992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108864

Other (OTH) AF: 0.0000333 AC: 2 AN: 60034

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152304 Hom.: 0 Cov.: 29 AF XY: 0.0000671 AC XY: 5 AN XY: 74470

African (AFR) AF: 0.0000481 AC: 2 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000419 AC: 5

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	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.48	T
PhyloP100		1.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.82
MPC		1.3
ClinPred		0.79	D
GERP RS		2.6
Varity_R		0.72
gMVP		0.69
Mutation Taster		=70/30	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: rs369109023; hg19: chr10-134941936;