4-22387758-C-T

Position:

• chr4-22387758-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The ENST00000334304.10(ADGRA3):​c.3913G>A​(p.Asp1305Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: ADGRA3 ENST00000334304.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31323457).
• 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.3913G>A	p.Asp1305Asn	missense_variant	19/19	ENST00000334304.10	NP_660333.2
ADGRA3	XM_047449703.1	c.3322G>A	p.Asp1108Asn	missense_variant	19/19		XP_047305659.1
ADGRA3	XM_047449704.1	c.3322G>A	p.Asp1108Asn	missense_variant	19/19		XP_047305660.1
ADGRA3	XM_011513811.3	c.3235G>A	p.Asp1079Asn	missense_variant	14/14		XP_011512113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRA3	ENST00000334304.10	c.3913G>A	p.Asp1305Asn	missense_variant	19/19	1	NM_145290.4	ENSP00000334952	P1
ADGRA3	ENST00000282943.9	n.3484G>A		non_coding_transcript_exon_variant	17/17	1
ADGRA3	ENST00000499527.6	n.3610G>A		non_coding_transcript_exon_variant	3/3	1
ADGRA3	ENST00000511051.5	c.104+1330G>A		intron_variant, NMD_transcript_variant		3		ENSP00000424927

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251162 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135740

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727172

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00

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

Jul 29, 2022

ClinVar contains an entry for this variant (Variation ID: 1524927). 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: "Benign"; 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 0.003%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1305 of the ADGRA3 protein (p.Asp1305Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.040	D
Polyphen		0.91	P
Vest4		0.35
MutPred		0.42		Gain of MoRF binding (P = 0.0584);
MVP		0.52
MPC		0.14
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.14
gMVP		0.16

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: rs928853508; hg19: chr4-22389381; COSMIC: COSV51561936; COSMIC: COSV51561936;