4-22387720-G-C

Position:

chr4-22387720-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_145290.4(ADGRA3):c.3951C>G(p.His1317Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,452,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000055 ( 0 hom. )

Consequence

ADGRA3
NM_145290.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.09

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:

ADGRA3 (HGNC:):

ADGRA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27412486).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRA3	NM_145290.4 linkuse as main transcript	c.3951C>G	p.His1317Gln	missense_variant	19/19	ENST00000334304.10	NP_660333.2	Q8IWK6-1
ADGRA3	XM_047449703.1 linkuse as main transcript	c.3360C>G	p.His1120Gln	missense_variant	19/19		XP_047305659.1
ADGRA3	XM_047449704.1 linkuse as main transcript	c.3360C>G	p.His1120Gln	missense_variant	19/19		XP_047305660.1
ADGRA3	XM_011513811.3 linkuse as main transcript	c.3273C>G	p.His1091Gln	missense_variant	14/14		XP_011512113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADGRA3	ENST00000334304.10 linkuse as main transcript	c.3951C>G	p.His1317Gln	missense_variant	19/19	1	NM_145290.4	ENSP00000334952.5	Q8IWK6-1
ADGRA3	ENST00000282943.9 linkuse as main transcript	n.3522C>G		non_coding_transcript_exon_variant	17/17	1
ADGRA3	ENST00000499527.6 linkuse as main transcript	n.3648C>G		non_coding_transcript_exon_variant	3/3	1
ADGRA3	ENST00000511051.5 linkuse as main transcript	n.104+1368C>G		intron_variant		3		ENSP00000424927.1	D6RER4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000809

AC:

AN:

247128

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133564

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000551

AC:

AN:

1452162

Hom.:

Cov.:

AF XY:

0.00000694

AC XY:

AN XY:

720898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

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

Oct 19, 2022

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1317 of the ADGRA3 protein (p.His1317Gln). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ADGRA3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Benign

0.19

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.78

M_CAP

Benign

0.051

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.72

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.5

REVEL

Benign

0.25

Sift

Benign

0.16

Sift4G

Benign

0.076

Polyphen

1.0

Vest4

0.57

MutPred

0.17

Gain of solvent accessibility (P = 0.0338);

MVP

0.093

MPC

0.52

ClinPred

0.35

GERP RS

-3.2

Varity_R

0.093

gMVP

0.51

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