chrX-136344815-C-T

Position:

• chrX-136344815-C-T

Variant summary

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

The NM_153834.4(ADGRG4):​c.1109C>T​(p.Pro370Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92

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=0.065218836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG4	NM_153834.4	c.1109C>T	p.Pro370Leu	missense_variant	6/26	ENST00000394143.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG4	ENST00000394143.6	c.1109C>T	p.Pro370Leu	missense_variant	6/26	1	NM_153834.4	P1
ADGRG4	ENST00000394141.1	c.494C>T	p.Pro165Leu	missense_variant	3/23	1
ADGRG4	ENST00000370652.5	c.1109C>T	p.Pro370Leu	missense_variant	4/24	5		P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The c.1109C>T (p.P370L) alteration is located in exon 6 (coding exon 3) of the ADGRG4 gene. This alteration results from a C to T substitution at nucleotide position 1109, causing the proline (P) at amino acid position 370 to be replaced by a leucine (L). 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	0.080
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.015	T;T;.
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.60	.;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.040
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.033	B;B;B
Vest4		0.15
MutPred		0.10		Loss of glycosylation at P370 (P = 0.0422);Loss of glycosylation at P370 (P = 0.0422);.;
MVP		0.030
MPC		0.036
ClinPred		0.16	T
GERP RS		4.0
Varity_R		0.076
gMVP		0.25

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-135426974; COSMIC: COSV54963226;