4-22387800-G-A

Position:

chr4-22387800-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000334304.10(ADGRA3):c.3871C>T(p.Pro1291Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADGRA3
ENST00000334304.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.11

Variant links:

Genes affected

ADGRA3 (HGNC:13839): (adhesion G protein-coupled receptor A3) This gene encodes a member of the G protein-coupled receptor superfamily. This membrane protein may play a role in tumor angiogenesis through its interaction with the human homolog of the Drosophila disc large tumor suppressor gene. This gene is mapped to a candidate region of chromosome 4 which may be associated with bipolar disorder and schizophrenia. [provided by RefSeq, Oct 2012]

ADGRA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0700106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADGRA3	NM_145290.4 linkuse as main transcript	c.3871C>T	p.Pro1291Ser	missense_variant	19/19	ENST00000334304.10	NP_660333.2
ADGRA3	XM_047449703.1 linkuse as main transcript	c.3280C>T	p.Pro1094Ser	missense_variant	19/19		XP_047305659.1
ADGRA3	XM_047449704.1 linkuse as main transcript	c.3280C>T	p.Pro1094Ser	missense_variant	19/19		XP_047305660.1
ADGRA3	XM_011513811.3 linkuse as main transcript	c.3193C>T	p.Pro1065Ser	missense_variant	14/14		XP_011512113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRA3	ENST00000334304.10 linkuse as main transcript	c.3871C>T	p.Pro1291Ser	missense_variant	19/19	1	NM_145290.4	ENSP00000334952	P1	Q8IWK6-1
ADGRA3	ENST00000282943.9 linkuse as main transcript	n.3442C>T		non_coding_transcript_exon_variant	17/17	1
ADGRA3	ENST00000499527.6 linkuse as main transcript	n.3568C>T		non_coding_transcript_exon_variant	3/3	1
ADGRA3	ENST00000511051.5 linkuse as main transcript	c.104+1288C>T		intron_variant, NMD_transcript_variant		3		ENSP00000424927

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251306

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ADGRA3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 1291 of the ADGRA3 protein (p.Pro1291Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.10

Eigen

Benign

-0.052

Eigen_PC

Benign

0.094

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

M_CAP

Benign

0.012

MetaRNN

Benign

0.070

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.080

REVEL

Benign

0.11

Sift

Benign

0.25

Sift4G

Benign

0.68

Polyphen

0.17

Vest4

0.31

MutPred

0.29

Loss of methylation at K1293 (P = 0.0589);

MVP

0.043

MPC

0.12

ClinPred

0.23

GERP RS

4.8

Varity_R

0.11

gMVP

0.085

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over