X-136323174-G-A

Variant names:

• chrX-136323174-G-A
• NM_153834.4:c.467G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_153834.4(ADGRG4):​c.467G>A​(p.Gly156Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG4	NM_153834.4	c.467G>A	p.Gly156Glu	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.467G>A	p.Gly156Glu	missense_variant	Exon 5 of 26	1	NM_153834.4	ENSP00000377699.1
ADGRG4	ENST00000394141.1	c.70+14327G>A		intron_variant	Intron 2 of 22	1		ENSP00000377697.1
ADGRG4	ENST00000370652.5	c.467G>A	p.Gly156Glu	missense_variant	Exon 3 of 24	5		ENSP00000359686.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.467G>A (p.G156E) alteration is located in exon 5 (coding exon 2) of the ADGRG4 gene. This alteration results from a G to A substitution at nucleotide position 467, causing the glycine (G) at amino acid position 156 to be replaced by a glutamic acid (E). 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	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.62	.;T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.40	T
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.75		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.088
MPC		0.29
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.74
gMVP		0.86

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-135405333;