rs138853777

Variant names:

• chrX-136323387-G-A
• rs138853777
• NM_153834.4:c.680G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-136323387-G-A
• chrX-136323387-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_153834.4(ADGRG4):​c.680G>A​(p.Arg227His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000184 in 1,196,669 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 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. R227S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 6 hem.)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.678
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14755738).
• BS2: High AC in GnomAd4 at 9 AD gene.

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.680G>A	p.Arg227His	missense	Exon 5 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.680G>A	p.Arg227His	missense	Exon 5 of 26	ENSP00000377699.1	Q8IZF6-1
	ADGRG4	ENST00000394141.1	TSL:1	c.70+14540G>A		intron	N/A	ENSP00000377697.1	Q8IZF6-3
	ADGRG4	ENST00000370652.5	TSL:5	c.680G>A	p.Arg227His	missense	Exon 3 of 24	ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes AF: 0.0000807 AC: 9 AN: 111472 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000954

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000293 AC: 5 AN: 170819 AF XY: 0.0000345

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000734

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 13 AN: 1085139 Hom.: 0 Cov.: 30 AF XY: 0.0000170 AC XY: 6 AN XY: 352677

African (AFR) AF: 0.0000385 AC: 1 AN: 25975

American (AMR) AF: 0.00 AC: 0 AN: 33822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18628

East Asian (EAS) AF: 0.00 AC: 0 AN: 30094

South Asian (SAS) AF: 0.0000194 AC: 1 AN: 51665

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4054

European-Non Finnish (NFE) AF: 0.0000120 AC: 10 AN: 835218

Other (OTH) AF: 0.0000220 AC: 1 AN: 45517

GnomAD4 genome AF: 0.0000807 AC: 9 AN: 111530 Hom.: 0 Cov.: 22 AF XY: 0.0000297 AC XY: 1 AN XY: 33726

African (AFR) AF: 0.000228 AC: 7 AN: 30686

American (AMR) AF: 0.0000952 AC: 1 AN: 10500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6005

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53098

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

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	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.68
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.16
Sift	Benign	0.067	T
Sift4G	Uncertain	0.012	D
Polyphen		0.90	P
Vest4		0.33
MVP		0.28
MPC		0.041
ClinPred		0.10	T
GERP RS		4.6
Varity_R		0.16
gMVP		0.11
Mutation Taster		=100/0	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: rs138853777; hg19: chrX-135405546;