4-22387764-C-A

Position:

chr4-22387764-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000334304.10(ADGRA3):c.3907G>T(p.Gly1303Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,016 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1303S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

ADGRA3
ENST00000334304.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.988

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028482854).

BS2

High AC in GnomAd4 at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADGRA3	NM_145290.4 linkuse as main transcript	c.3907G>T	p.Gly1303Cys	missense_variant	19/19	ENST00000334304.10	NP_660333.2
ADGRA3	XM_047449703.1 linkuse as main transcript	c.3316G>T	p.Gly1106Cys	missense_variant	19/19		XP_047305659.1
ADGRA3	XM_047449704.1 linkuse as main transcript	c.3316G>T	p.Gly1106Cys	missense_variant	19/19		XP_047305660.1
ADGRA3	XM_011513811.3 linkuse as main transcript	c.3229G>T	p.Gly1077Cys	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.3907G>T	p.Gly1303Cys	missense_variant	19/19	1	NM_145290.4	ENSP00000334952	P1	Q8IWK6-1
ADGRA3	ENST00000282943.9 linkuse as main transcript	n.3478G>T		non_coding_transcript_exon_variant	17/17	1
ADGRA3	ENST00000499527.6 linkuse as main transcript	n.3604G>T		non_coding_transcript_exon_variant	3/3	1
ADGRA3	ENST00000511051.5 linkuse as main transcript	c.104+1324G>T		intron_variant, NMD_transcript_variant		3		ENSP00000424927

Frequencies

GnomAD3 genomes

AF:

0.000809

AC:

123

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000709

AC:

178

AN:

251208

Hom.:

AF XY:

0.000597

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.000740

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.00131

AC:

1922

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

880

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.000711

Gnomad4 NFE exome

AF:

0.00159

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.000808

AC:

123

AN:

152242

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00107

Hom.:

Bravo

AF:

0.000714

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.000642

AC:

EpiCase

AF:

0.00120

EpiControl

AF:

0.00142

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.3907G>T (p.G1303C) alteration is located in exon 19 (coding exon 19) of the ADGRA3 gene. This alteration results from a G to T substitution at nucleotide position 3907, causing the glycine (G) at amino acid position 1303 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1303 of the ADGRA3 protein (p.Gly1303Cys). This variant is present in population databases (rs147716223, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ADGRA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 839957). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Retinal dystrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.036

MetaRNN

Benign

0.028

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.057

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.018

Polyphen

0.65

Vest4

0.14

MVP

0.068

MPC

0.25

ClinPred

0.048

GERP RS

0.65

Varity_R

0.16

gMVP

0.18

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