X-136323368-A-G

Variant names:

• chrX-136323368-A-G
• rs145079154
• NM_153834.4:c.661A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_153834.4(ADGRG4):​c.661A>G​(p.Thr221Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,206,729 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 58 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 0.00012 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00015 (0 hom. 55 hem.)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.668
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047343552).
• BS2: High AC in GnomAd4 at 13 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.661A>G	p.Thr221Ala	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.661A>G	p.Thr221Ala	missense	Exon 5 of 26	ENSP00000377699.1	Q8IZF6-1
	ADGRG4	ENST00000394141.1	TSL:1	c.70+14521A>G		intron	N/A	ENSP00000377697.1	Q8IZF6-3
	ADGRG4	ENST00000370652.5	TSL:5	c.661A>G	p.Thr221Ala	missense	Exon 3 of 24	ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111139 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000656

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000196 AC: 35 AN: 178222 AF XY: 0.000203

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000738

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.000145

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000150 AC: 164 AN: 1095590 Hom.: 0 Cov.: 30 AF XY: 0.000152 AC XY: 55 AN XY: 361068

African (AFR) AF: 0.0000759 AC: 2 AN: 26334

American (AMR) AF: 0.000171 AC: 6 AN: 35015

Ashkenazi Jewish (ASJ) AF: 0.00109 AC: 21 AN: 19224

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 53608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.000149 AC: 125 AN: 840627

Other (OTH) AF: 0.000174 AC: 8 AN: 46004

GnomAD4 genome AF: 0.000117 AC: 13 AN: 111139 Hom.: 0 Cov.: 22 AF XY: 0.0000900 AC XY: 3 AN XY: 33349

African (AFR) AF: 0.0000656 AC: 2 AN: 30511

American (AMR) AF: 0.00 AC: 0 AN: 10442

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 3 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5964

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

European-Non Finnish (NFE) AF: 0.000151 AC: 8 AN: 53015

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.000391 Hom.: 3

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000148 AC: 18

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	-0.46	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.67
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.093
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.19
MVP		0.21
MPC		0.035
ClinPred		0.083	T
GERP RS		4.5
Varity_R		0.18
gMVP		0.11
Mutation Taster		=98/2	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: rs145079154; hg19: chrX-135405527;