Genetic Variant ADGRG4:p.Ala93Thr (chrX-136322984-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_153834.4(ADGRG4):c.277G>A(p.Ala93Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,209,965 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 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., 1 hem., cov: 23)

Exomes 𝑓: 0.000035 ( 0 hom. 16 hem. )

Consequence

ADGRG4
NM_153834.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04691848).

BS2

High Hemizygotes in GnomAdExome4 at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG4	NM_153834.4 link	c.277G>A	p.Ala93Thr	missense_variant	Exon 5 of 26	ENST00000394143.6	NP_722576.3	Q8IZF6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADGRG4	ENST00000394143.6 link	c.277G>A	p.Ala93Thr	missense_variant	Exon 5 of 26	1	NM_153834.4	ENSP00000377699.1	Q8IZF6-1
ADGRG4	ENST00000394141.1 link	c.70+14137G>A		intron_variant	Intron 2 of 22	1		ENSP00000377697.1	Q8IZF6-3
ADGRG4	ENST00000370652.5 link	c.277G>A	p.Ala93Thr	missense_variant	Exon 3 of 24	5		ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes

AF:

0.0000267

AC:

AN:

112191

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34343

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00113

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

GnomAD3 exomes

AF:

0.0000983

AC:

AN:

183172

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

67686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00201

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000346

AC:

AN:

1097774

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

363128

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00150

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.0000267

AC:

AN:

112191

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34343

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00113

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000521

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.277G>A (p.A93T) alteration is located in exon 5 (coding exon 2) of the ADGRG4 gene. This alteration results from a G to A substitution at nucleotide position 277, causing the alanine (A) at amino acid position 93 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

T;T

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.61

.;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.034

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

0.75

P;P

Vest4

0.31

MutPred

0.39

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

0.18

MPC

0.24

ClinPred

0.10

GERP RS

4.8

Varity_R

0.43

gMVP

0.28

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over