Variant X-136308838-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_153834.4(ADGRG4):c.61T>C(p.Phe21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000914 in 985,074 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000091 ( 0 hom. 7 hem. )

Consequence

ADGRG4
NM_153834.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.14

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23003456).

BS2

High Hemizygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ADGRG4	NM_153834.4 linkuse as main transcript	c.61T>C	p.Phe21Leu	missense_variant	4/26	ENST00000394143.6
ADGRG4	XM_011531269.3 linkuse as main transcript	c.61T>C	p.Phe21Leu	missense_variant	2/24
ADGRG4	XM_047441830.1 linkuse as main transcript	c.61T>C	p.Phe21Leu	missense_variant	2/23
ADGRG4	XM_047441831.1 linkuse as main transcript	c.61T>C	p.Phe21Leu	missense_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG4	ENST00000394143.6 linkuse as main transcript	c.61T>C	p.Phe21Leu	missense_variant	4/26	1	NM_153834.4	P1	Q8IZF6-1
ADGRG4	ENST00000394141.1 linkuse as main transcript	c.61T>C	p.Phe21Leu	missense_variant	2/23	1			Q8IZF6-3
ADGRG4	ENST00000370652.5 linkuse as main transcript	c.61T>C	p.Phe21Leu	missense_variant	2/24	5		P1	Q8IZF6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000111

AC:

AN:

180655

Hom.:

AF XY:

0.0000306

AC XY:

AN XY:

65403

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000914

AC:

AN:

985074

Hom.:

Cov.:

AF XY:

0.0000245

AC XY:

AN XY:

285408

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000122

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000494

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

Apr 17, 2024

The c.61T>C (p.F21L) alteration is located in exon 4 (coding exon 1) of the ADGRG4 gene. This alteration results from a T to C substitution at nucleotide position 61, causing the phenylalanine (F) at amino acid position 21 to be replaced by a leucine (L). 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

Pathogenic

0.66

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

T;T;.

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.53

.;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;N;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.043

D;D;D

Sift4G

Uncertain

0.051

T;T;T

Polyphen

0.80

P;P;P

Vest4

0.50

MutPred

0.23

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);

MVP

0.29

MPC

0.040

ClinPred

0.36

GERP RS

4.3

Varity_R

0.23

gMVP

0.20

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