X-136308788-A-G

Position:

• chrX-136308788-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_153834.4(ADGRG4):​c.11A>G​(p.His4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000191 in 1,047,969 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.27

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05968848).
• BP6: Variant X-136308788-A-G is Benign according to our data. Variant chrX-136308788-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3271847.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG4	NM_153834.4	c.11A>G	p.His4Arg	missense_variant	4/26	ENST00000394143.6
ADGRG4	XM_011531269.3	c.11A>G	p.His4Arg	missense_variant	2/24
ADGRG4	XM_047441830.1	c.11A>G	p.His4Arg	missense_variant	2/23
ADGRG4	XM_047441831.1	c.11A>G	p.His4Arg	missense_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG4	ENST00000394143.6	c.11A>G	p.His4Arg	missense_variant	4/26	1	NM_153834.4	P1
ADGRG4	ENST00000394141.1	c.11A>G	p.His4Arg	missense_variant	2/23	1
ADGRG4	ENST00000370652.5	c.11A>G	p.His4Arg	missense_variant	2/24	5		P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000191 AC: 2 AN: 1047969 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 326297

Gnomad4 AFR exome AF: 0.0000395

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: 0.00

Gnomad4 OTH exome AF: 0.0000225

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.3
DANN	Benign	0.22
DEOGEN2	Benign	0.011	T;T;.
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.36	.;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.061
Sift	Benign	0.11	T;T;D
Sift4G	Benign	0.65	T;T;.
Polyphen		0.0	B;B;B
Vest4		0.17
MutPred		0.33		Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);
MVP		0.092
MPC		0.039
ClinPred		0.048	T
GERP RS		1.8
Varity_R		0.079
gMVP		0.49

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: rs894826241; hg19: chrX-135390947;