X-136322826-A-G

Variant names:

• chrX-136322826-A-G
• NM_153834.4:c.119A>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_153834.4(ADGRG4):​c.119A>G​(p.Asp40Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,087,345 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 3 hem.)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

Genes affected

ADGRG4 (HGNC:18992): (adhesion G protein-coupled receptor G4) This gene encodes a G-protein coupled receptor belonging to a large family of diverse integral membrane proteins that participate in various physiological functions. Members of this superfamily are characterized by a signature 7-transmembrane domain motif. The ligand for this family member is unknown, and it is therefore an orphan receptor. This receptor is known to be expressed in normal enterochromaffin cells and in gastrointestinal neuroendocrine carcinoma cells, and it is therefore considered to be a novel biomarker or target for immunotherapy. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG4	NM_153834.4	c.119A>G	p.Asp40Gly	missense_variant	Exon 5 of 26	ENST00000394143.6	NP_722576.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG4	ENST00000394143.6	c.119A>G	p.Asp40Gly	missense_variant	Exon 5 of 26	1	NM_153834.4	ENSP00000377699.1
ADGRG4	ENST00000394141.1	c.70+13979A>G		intron_variant	Intron 2 of 22	1		ENSP00000377697.1
ADGRG4	ENST00000370652.5	c.119A>G	p.Asp40Gly	missense_variant	Exon 3 of 24	5		ENSP00000359686.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1087345 Hom.: 0 Cov.: 29 AF XY: 0.00000846 AC XY: 3 AN XY: 354621

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: 0.00000359

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119A>G (p.D40G) alteration is located in exon 5 (coding exon 2) of the ADGRG4 gene. This alteration results from a A to G substitution at nucleotide position 119, causing the aspartic acid (D) at amino acid position 40 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.53	.;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.49	T
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		0.99	D;D
Vest4		0.61
MutPred		0.58		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.081
MPC		0.22
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.71

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: chrX-135404985;