chrX-136344809-C-G

Variant names:

• chrX-136344809-C-G
• rs5930931
• NM_153834.4:c.1103C>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_153834.4(ADGRG4):​c.1103C>G​(p.Pro368Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,094,375 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P368H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 4 hem.)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.324

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06944218).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG4	NM_153834.4	c.1103C>G	p.Pro368Arg	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.1103C>G	p.Pro368Arg	missense_variant	Exon 6 of 26	1	NM_153834.4	ENSP00000377699.1
ADGRG4	ENST00000394141.1	c.488C>G	p.Pro163Arg	missense_variant	Exon 3 of 23	1		ENSP00000377697.1
ADGRG4	ENST00000370652.5	c.1103C>G	p.Pro368Arg	missense_variant	Exon 4 of 24	5		ENSP00000359686.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181345 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66259

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: 0.0000531

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 6 AN: 1094375 Hom.: 0 Cov.: 32 AF XY: 0.0000111 AC XY: 4 AN XY: 359963

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: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.8
DANN	Benign	0.86
DEOGEN2	Benign	0.012	T;T;.
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.39	.;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Benign	0.053
Sift	Uncertain	0.029	D;D;D
Sift4G	Uncertain	0.058	T;T;D
Polyphen		0.40	B;B;P
Vest4		0.19
MutPred		0.17		Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);.;
MVP		0.030
MPC		0.037
ClinPred		0.075	T
GERP RS		2.1
Varity_R		0.079
gMVP		0.11

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: rs5930931; hg19: chrX-135426968;