Genetic Variant ADGRG4:p.Pro368Arg (chrX-136344809-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_153834.4(ADGRG4):c.1103C>G(p.Pro368Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,094,375 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 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: not found (cov: 23)

Exomes 𝑓: 0.0000055 ( 0 hom. 4 hem. )

Consequence

ADGRG4
NM_153834.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.324

Publications

29 publications found

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 Gene-Disease associations (from GenCC):

autism spectrum disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ADGRG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06944218).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG4	NM_153834.4 link	c.1103C>G	p.Pro368Arg	missense_variant	Exon 6 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.1103C>G	p.Pro368Arg	missense_variant	Exon 6 of 26	1	NM_153834.4	ENSP00000377699.1	Q8IZF6-1
ADGRG4	ENST00000394141.1 link	c.488C>G	p.Pro163Arg	missense_variant	Exon 3 of 23	1		ENSP00000377697.1	Q8IZF6-3
ADGRG4	ENST00000370652.5 link	c.1103C>G	p.Pro368Arg	missense_variant	Exon 4 of 24	5		ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000551

AC:

AN:

181345

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1094375

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

359963

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26332

American (AMR)

AF:

0.00

AC:

AN:

35087

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19331

East Asian (EAS)

AF:

0.00

AC:

AN:

30170

South Asian (SAS)

AF:

0.0000927

AC:

AN:

53959

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4123

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

838998

Other (OTH)

AF:

0.0000218

AC:

AN:

45973

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.8

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.012

T;T;.

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.39

.;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.069

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

0.32

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.65

N;N;N

REVEL

Benign

0.053

Sift

Uncertain

0.029

D;D;D

Sift4G

Uncertain

0.058

T;T;D

Polyphen

0.40

B;B;P

Vest4

0.19

MutPred

0.17

Gain of MoRF binding (P = 0.0276);Gain of MoRF binding (P = 0.0276);.;

MVP

0.030

MPC

0.037

ClinPred

0.075

GERP RS

2.1

Varity_R

0.079

gMVP

0.11

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over