chr4-22387794-T-C

Position:

• chr4-22387794-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000334304.10(ADGRA3):​c.3877A>G​(p.Lys1293Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRA3 ENST00000334304.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.59

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3357534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRA3	NM_145290.4	c.3877A>G	p.Lys1293Glu	missense_variant	19/19	ENST00000334304.10	NP_660333.2
ADGRA3	XM_047449703.1	c.3286A>G	p.Lys1096Glu	missense_variant	19/19		XP_047305659.1
ADGRA3	XM_047449704.1	c.3286A>G	p.Lys1096Glu	missense_variant	19/19		XP_047305660.1
ADGRA3	XM_011513811.3	c.3199A>G	p.Lys1067Glu	missense_variant	14/14		XP_011512113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRA3	ENST00000334304.10	c.3877A>G	p.Lys1293Glu	missense_variant	19/19	1	NM_145290.4	ENSP00000334952	P1
ADGRA3	ENST00000282943.9	n.3448A>G		non_coding_transcript_exon_variant	17/17	1
ADGRA3	ENST00000499527.6	n.3574A>G		non_coding_transcript_exon_variant	3/3	1
ADGRA3	ENST00000511051.5	c.104+1294A>G		intron_variant, NMD_transcript_variant		3		ENSP00000424927

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 07, 2022

This variant has not been reported in the literature in individuals affected with ADGRA3-related conditions. 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 is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1293 of the ADGRA3 protein (p.Lys1293Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.032
Eigen_PC	Benign	0.0061
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.20
Sift	Benign	0.043	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.66	P
Vest4		0.54
MutPred		0.28		Loss of ubiquitination at K1293 (P = 0.0081);
MVP		0.043
MPC		0.16
ClinPred		0.86	D
GERP RS		3.1
Varity_R		0.22
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-22389417;