Genetic Variant ADGRG4:p.Arg227Cys (chrX-136323386-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_153834.4(ADGRG4):c.679C>T(p.Arg227Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,085,631 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.000032 ( 0 hom. 7 hem. )

Consequence

ADGRG4
NM_153834.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.12

Publications

3 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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 35 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153834.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG4	NM_153834.4	MANE Select	c.679C>T	p.Arg227Cys	missense	Exon 5 of 26	NP_722576.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRG4	ENST00000394143.6	TSL:1 MANE Select	c.679C>T	p.Arg227Cys	missense	Exon 5 of 26	ENSP00000377699.1	Q8IZF6-1
ADGRG4	ENST00000394141.1	TSL:1	c.70+14539C>T		intron	N/A	ENSP00000377697.1	Q8IZF6-3
ADGRG4	ENST00000370652.5	TSL:5	c.679C>T	p.Arg227Cys	missense	Exon 3 of 24	ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000117

AC:

AN:

171467

AF XY:

0.0000171

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:

0.0000262

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1085631

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

353067

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25979

American (AMR)

AF:

0.00

AC:

AN:

33872

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18678

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30086

South Asian (SAS)

AF:

0.00

AC:

AN:

51809

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40211

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4049

European-Non Finnish (NFE)

AF:

0.0000407

AC:

AN:

835412

Other (OTH)

AF:

0.00

AC:

AN:

45535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.044

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.65

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-1.1

PhyloP100

1.1

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.28

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.42

Vest4

0.69

MVP

0.12

MPC

0.24

ClinPred

0.68

GERP RS

4.8

Varity_R

0.52

gMVP

0.20

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over