rs5930931

chrX-136344809-C-AchrX-136344809-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153834.4(ADGRG4):c.1103C>A(p.Pro368His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,205,088 control chromosomes in the GnomAD database, including 88,305 homozygotes. There are 183,084 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (9309 hom., 15710 hem., cov: 23)
  • Exomes 𝑓: 0.46 (78996 hom. 167374 hem.)
• Consequence: ADGRG4 NM_153834.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.324

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.132889E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG4	NM_153834.4	c.1103C>A	p.Pro368His	missense_variant	6/26	ENST00000394143.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG4	ENST00000394143.6	c.1103C>A	p.Pro368His	missense_variant	6/26	1	NM_153834.4	P1
ADGRG4	ENST00000394141.1	c.488C>A	p.Pro163His	missense_variant	3/23	1
ADGRG4	ENST00000370652.5	c.1103C>A	p.Pro368His	missense_variant	4/24	5		P1

Frequencies

GnomAD3 genomes AF: 0.480 AC: 53304 AN: 111002 Hom.: 9308 Cov.: 23 AF XY: 0.471 AC XY: 15678 AN XY: 33278

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.476

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.467

Gnomad OTH AF: 0.523

GnomAD3 exomes AF: 0.442 AC: 80089 AN: 181345 Hom.: 11473 AF XY: 0.443 AC XY: 29324 AN XY: 66259

Gnomad AFR exome AF: 0.544

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.472

Gnomad EAS exome AF: 0.256

Gnomad SAS exome AF: 0.469

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.466

GnomAD4 exome AF: 0.463 AC: 506931 AN: 1094031 Hom.: 78996 Cov.: 32 AF XY: 0.465 AC XY: 167374 AN XY: 359915

Gnomad4 AFR exome AF: 0.536

Gnomad4 AMR exome AF: 0.417

Gnomad4 ASJ exome AF: 0.478

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.465

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.470

Gnomad4 OTH exome AF: 0.467

GnomAD4 genome AF: 0.480 AC: 53337 AN: 111057 Hom.: 9309 Cov.: 23 AF XY: 0.471 AC XY: 15710 AN XY: 33343

Gnomad4 AFR AF: 0.543

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.479

Gnomad4 EAS AF: 0.273

Gnomad4 SAS AF: 0.474

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.467

Gnomad4 OTH AF: 0.524

Alfa AF: 0.467 Hom.: 49849

Bravo AF: 0.484

TwinsUK AF: 0.466 AC: 1727

ALSPAC AF: 0.454 AC: 1311

ESP6500AA AF: 0.543 AC: 2081

ESP6500EA AF: 0.476 AC: 3200

ExAC AF: 0.448 AC: 54379

EpiCase AF: 0.485

EpiControl AF: 0.487

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.91	T
BayesDel_noAF	Benign	-0.94
Cadd	Benign	9.7
Dann	Benign	0.96
DEOGEN2	Benign	0.012	T;T;.
FATHMM_MKL	Benign	0.030	N
MetaRNN	Benign	0.00011	T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.82	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.085	T;T;T
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.88	P;P;P
Vest4		0.069
MPC		0.046
ClinPred		0.0067	T
GERP RS		2.1
Varity_R		0.095
gMVP		0.10

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

Publications

LitVar

Other links and lift over

dbSNP: rs5930931; hg19: chrX-135426968; COSMIC: COSV54956149;