X-136349077-T-C

Variant names:

• chrX-136349077-T-C
• rs5930932
• NM_153834.4:c.5371T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153834.4(ADGRG4):​c.5371T>C​(p.Phe1791Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,094,075 control chromosomes in the GnomAD database, including 82,105 homozygotes. There are 170,593 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (10098 hom., 15741 hem., cov: 22)
  • Exomes 𝑓: 0.47 (82105 hom. 170593 hem.)
  • Failed GnomAD Quality Control
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.794
• Publications: 23 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7827749E-4).
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG4	NM_153834.4	c.5371T>C	p.Phe1791Leu	missense_variant	Exon 6 of 26	ENST00000394143.6	NP_722576.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG4	ENST00000394143.6	c.5371T>C	p.Phe1791Leu	missense_variant	Exon 6 of 26	1	NM_153834.4	ENSP00000377699.1
ADGRG4	ENST00000394141.1	c.4756T>C	p.Phe1586Leu	missense_variant	Exon 3 of 23	1		ENSP00000377697.1
ADGRG4	ENST00000370652.5	c.5371T>C	p.Phe1791Leu	missense_variant	Exon 4 of 24	5		ENSP00000359686.1

Frequencies

GnomAD3 genomes AF: 0.499 AC: 54871 AN: 109966 Hom.: 10097 Cov.: 22

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.581

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.540

GnomAD2 exomes AF: 0.462 AC: 82567 AN: 178694 AF XY: 0.466

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.407

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.475

Gnomad OTH exome AF: 0.481

GnomAD4 exome AF: 0.472 AC: 516862 AN: 1094075 Hom.: 82105 Cov.: 33 AF XY: 0.473 AC XY: 170593 AN XY: 360697

African (AFR) AF: 0.582 AC: 15280 AN: 26243

American (AMR) AF: 0.423 AC: 14753 AN: 34857

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 9317 AN: 19221

East Asian (EAS) AF: 0.417 AC: 12590 AN: 30187

South Asian (SAS) AF: 0.469 AC: 25095 AN: 53542

European-Finnish (FIN) AF: 0.424 AC: 17163 AN: 40452

Middle Eastern (MID) AF: 0.541 AC: 2222 AN: 4107

European-Non Finnish (NFE) AF: 0.474 AC: 398285 AN: 839526

Other (OTH) AF: 0.482 AC: 22157 AN: 45940

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.499 AC: 54909 AN: 110024 Hom.: 10098 Cov.: 22 AF XY: 0.486 AC XY: 15741 AN XY: 32372

African (AFR) AF: 0.587 AC: 17765 AN: 30264

American (AMR) AF: 0.475 AC: 4917 AN: 10344

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1283 AN: 2622

East Asian (EAS) AF: 0.387 AC: 1328 AN: 3428

South Asian (SAS) AF: 0.469 AC: 1225 AN: 2613

European-Finnish (FIN) AF: 0.410 AC: 2365 AN: 5767

Middle Eastern (MID) AF: 0.596 AC: 127 AN: 213

European-Non Finnish (NFE) AF: 0.472 AC: 24814 AN: 52591

Other (OTH) AF: 0.540 AC: 816 AN: 1511

Alfa AF: 0.488 Hom.: 43718

Bravo AF: 0.508

TwinsUK AF: 0.471 AC: 1748

ALSPAC AF: 0.461 AC: 1332

ESP6500AA AF: 0.589 AC: 2257

ESP6500EA AF: 0.480 AC: 3229

ExAC AF: 0.466 AC: 56547

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-1.0	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.034
DANN	Benign	0.16
DEOGEN2	Benign	0.0027	T;T;.
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.24	.;T;T
MetaRNN	Benign	0.00018	T;T;T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.79
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.0	N;N;N
REVEL	Benign	0.0050
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.0040
MutPred		0.083		Gain of glycosylation at T1787 (P = 0.0852);Gain of glycosylation at T1787 (P = 0.0852);.;
MPC		0.038
ClinPred		0.00087	T
GERP RS		-1.8
Varity_R		0.036
gMVP		0.050
Mutation Taster		=100/0	polymorphism (auto)

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: rs5930932; hg19: chrX-135431236; COSMIC: COSV54951201;