4-22387796-A-G

Position:

• chr4-22387796-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_145290.4(ADGRA3):​c.3875T>C​(p.Ile1292Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,828 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: 0.000020 (0 hom.)
• Consequence: ADGRA3 NM_145290.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031541497).
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRA3	NM_145290.4	c.3875T>C	p.Ile1292Thr	missense_variant	19/19	ENST00000334304.10	NP_660333.2
ADGRA3	XM_047449703.1	c.3284T>C	p.Ile1095Thr	missense_variant	19/19		XP_047305659.1
ADGRA3	XM_047449704.1	c.3284T>C	p.Ile1095Thr	missense_variant	19/19		XP_047305660.1
ADGRA3	XM_011513811.3	c.3197T>C	p.Ile1066Thr	missense_variant	14/14		XP_011512113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRA3	ENST00000334304.10	c.3875T>C	p.Ile1292Thr	missense_variant	19/19	1	NM_145290.4	ENSP00000334952.5
ADGRA3	ENST00000282943.9	n.3446T>C		non_coding_transcript_exon_variant	17/17	1
ADGRA3	ENST00000499527.6	n.3572T>C		non_coding_transcript_exon_variant	3/3	1
ADGRA3	ENST00000511051.5	n.104+1292T>C		intron_variant		3		ENSP00000424927.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251292 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135804

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727210

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000234

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000731 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2021

This variant has not been reported in the literature in individuals affected with ADGRA3-related conditions. This variant is present in population databases (rs776404075, ExAC 0.003%). This sequence change replaces isoleucine with threonine at codon 1292 of the ADGRA3 protein (p.Ile1292Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.067
Sift	Benign	0.14	T
Sift4G	Benign	0.070	T
Polyphen		0.0	B
Vest4		0.017
MutPred		0.27		Gain of relative solvent accessibility (P = 0.0098);
MVP		0.043
MPC		0.13
ClinPred		0.27	T
GERP RS		1.8
Varity_R		0.024
gMVP		0.21

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

Other links and lift over

dbSNP: rs776404075; hg19: chr4-22389419;