NM_153834.4:c.794A>G

Variant names:

• chrX-136344500-A-G
• rs2074998620
• NM_153834.4:c.794A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153834.4(ADGRG4):​c.794A>G​(p.His265Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000183 in 1,093,103 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H265Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• Publications: 0 publications found

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]

ADGRG4 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08704266).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153834.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG4	NM_153834.4	MANE Select	c.794A>G	p.His265Arg	missense	Exon 6 of 26	NP_722576.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG4	ENST00000394143.6	TSL:1 MANE Select	c.794A>G	p.His265Arg	missense	Exon 6 of 26	ENSP00000377699.1	Q8IZF6-1
	ADGRG4	ENST00000394141.1	TSL:1	c.179A>G	p.His60Arg	missense	Exon 3 of 23	ENSP00000377697.1	Q8IZF6-3
	ADGRG4	ENST00000370652.5	TSL:5	c.794A>G	p.His265Arg	missense	Exon 4 of 24	ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093103 Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 1 AN XY: 358903

African (AFR) AF: 0.0000761 AC: 2 AN: 26294

American (AMR) AF: 0.00 AC: 0 AN: 35137

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19339

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53917

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40495

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837715

Other (OTH) AF: 0.00 AC: 0 AN: 45910

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.023	T
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.5
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.032
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.26	T
Polyphen		0.24	B
Vest4		0.18
MutPred		0.13		Loss of glycosylation at T263 (P = 0.0762)
MVP		0.085
MPC		0.069
ClinPred		0.22	T
GERP RS		2.8
Varity_R		0.12
gMVP		0.21
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs2074998620; hg19: chrX-135426659;