X-136323038-C-T

Variant names:

• chrX-136323038-C-T
• rs374820774
• NM_153834.4:c.331C>T

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.331C>T​(p.Arg111Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,209,734 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000082 (0 hom. 1 hem.)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0470
• Publications: 3 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=0.1915642).
• BS2: High AC in GnomAdExome4 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.331C>T	p.Arg111Cys	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.331C>T	p.Arg111Cys	missense	Exon 5 of 26	ENSP00000377699.1	Q8IZF6-1
	ADGRG4	ENST00000394141.1	TSL:1	c.70+14191C>T		intron	N/A	ENSP00000377697.1	Q8IZF6-3
	ADGRG4	ENST00000370652.5	TSL:5	c.331C>T	p.Arg111Cys	missense	Exon 3 of 24	ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111845 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000952

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183118 AF XY: 0.00

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1097889 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363247

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 841814

Other (OTH) AF: 0.00 AC: 0 AN: 46087

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111845 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34009

African (AFR) AF: 0.0000651 AC: 2 AN: 30742

American (AMR) AF: 0.0000952 AC: 1 AN: 10506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3580

South Asian (SAS) AF: 0.00 AC: 0 AN: 2663

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6057

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53207

Other (OTH) AF: 0.00 AC: 0 AN: 1511

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

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	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.87	T
PhyloP100		0.047
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.35
MVP		0.099
MPC		0.20
ClinPred		0.24	T
GERP RS		1.2
Varity_R		0.15
gMVP		0.46
Mutation Taster		=99/1	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: rs374820774; hg19: chrX-135405197;