X-136344491-A-G

Variant names:

• chrX-136344491-A-G
• NM_153834.4:c.785A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153834.4(ADGRG4):​c.785A>G​(p.Asn262Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,333 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.932

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052567154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG4	NM_153834.4	c.785A>G	p.Asn262Ser	missense_variant	Exon 6 of 26	ENST00000394143.6	NP_722576.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG4	ENST00000394143.6	c.785A>G	p.Asn262Ser	missense_variant	Exon 6 of 26	1	NM_153834.4	ENSP00000377699.1
ADGRG4	ENST00000394141.1	c.170A>G	p.Asn57Ser	missense_variant	Exon 3 of 23	1		ENSP00000377697.1
ADGRG4	ENST00000370652.5	c.785A>G	p.Asn262Ser	missense_variant	Exon 4 of 24	5		ENSP00000359686.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091333 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 357209

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: 0.00000120

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

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.785A>G (p.N262S) alteration is located in exon 6 (coding exon 3) of the ADGRG4 gene. This alteration results from a A to G substitution at nucleotide position 785, causing the asparagine (N) at amino acid position 262 to be replaced by a serine (S). 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	0.092
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	5.4
DANN	Benign	0.95
DEOGEN2	Benign	0.0043	T;T;.
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.31	.;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.095
Sift	Uncertain	0.0030	D;D;D
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.017
MutPred		0.14		Gain of glycosylation at N262 (P = 0.0352);Gain of glycosylation at N262 (P = 0.0352);.;
MVP		0.12
MPC		0.030
ClinPred		0.11	T
GERP RS		4.2
Varity_R		0.061
gMVP		0.059

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-135426650;