Variant X-136322789-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_153834.4(ADGRG4):c.82C>A(p.Leu28Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,181,237 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 68 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 0.00025 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00021 ( 0 hom. 66 hem. )

Consequence

ADGRG4
NM_153834.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.411

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=0.011846185).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG4	NM_153834.4 linkuse as main transcript	c.82C>A	p.Leu28Ile	missense_variant	5/26	ENST00000394143.6	NP_722576.3	Q8IZF6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADGRG4	ENST00000394143.6 linkuse as main transcript	c.82C>A	p.Leu28Ile	missense_variant	5/26	1	NM_153834.4	ENSP00000377699.1	Q8IZF6-1
ADGRG4	ENST00000394141.1 linkuse as main transcript	c.70+13942C>A		intron_variant		1		ENSP00000377697.1	Q8IZF6-3
ADGRG4	ENST00000370652.5 linkuse as main transcript	c.82C>A	p.Leu28Ile	missense_variant	3/24	5		ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

111884

Hom.:

Cov.:

AF XY:

0.0000587

AC XY:

AN XY:

34096

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000284

Gnomad ASJ

AF:

0.00452

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000166

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000226

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000376

AC:

AN:

157092

Hom.:

AF XY:

0.000416

AC XY:

AN XY:

50422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000222

Gnomad ASJ exome

AF:

0.00469

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000677

Gnomad NFE exome

AF:

0.000371

Gnomad OTH exome

AF:

0.000268

GnomAD4 exome

AF:

0.000214

AC:

229

AN:

1069299

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

AN XY:

344725

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000229

Gnomad4 ASJ exome

AF:

0.00392

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000753

Gnomad4 NFE exome

AF:

0.000157

Gnomad4 OTH exome

AF:

0.000379

GnomAD4 genome

AF:

0.000250

AC:

AN:

111938

Hom.:

Cov.:

AF XY:

0.0000585

AC XY:

AN XY:

34160

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000284

Gnomad4 ASJ

AF:

0.00452

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000166

Gnomad4 NFE

AF:

0.000226

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000579

Hom.:

Bravo

AF:

0.000208

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000429

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.82C>A (p.L28I) alteration is located in exon 5 (coding exon 2) of the ADGRG4 gene. This alteration results from a C to A substitution at nucleotide position 82, causing the leucine (L) at amino acid position 28 to be replaced by an isoleucine (I). 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

0.30

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.024

T;T

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.51

.;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.88

N;N

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.43

MVP

0.22

MPC

0.26

ClinPred

0.088

GERP RS

3.1

Varity_R

0.35

gMVP

0.40

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