chrX-136344491-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 14/20 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. N262D) has been classified as Uncertain significance.

• 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
• 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: Likely_benign. The variant received -2 ACMG points.

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

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.785A>G	p.Asn262Ser	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.785A>G	p.Asn262Ser	missense	Exon 6 of 26	ENSP00000377699.1	Q8IZF6-1
	ADGRG4	ENST00000394141.1	TSL:1	c.170A>G	p.Asn57Ser	missense	Exon 3 of 23	ENSP00000377697.1	Q8IZF6-3
	ADGRG4	ENST00000370652.5	TSL:5	c.785A>G	p.Asn262Ser	missense	Exon 4 of 24	ENSP00000359686.1	Q8IZF6-1

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

African (AFR) AF: 0.00 AC: 0 AN: 26275

American (AMR) AF: 0.00 AC: 0 AN: 35122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19313

East Asian (EAS) AF: 0.00 AC: 0 AN: 30166

South Asian (SAS) AF: 0.00 AC: 0 AN: 53886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40487

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4109

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 836109

Other (OTH) AF: 0.00 AC: 0 AN: 45866

GnomAD4 genome Cov.: 22

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	0.092
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	5.4
DANN	Benign	0.95
DEOGEN2	Benign	0.0043	T
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.93
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.095
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.017
MutPred		0.14		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
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

hg19: chrX-135426650;