Genetic Variant ADGRG4:p.Ser253Tyr (chrX-136344464-C-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_153834.4(ADGRG4):c.758C>A(p.Ser253Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000885 in 1,186,534 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 60 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000094 ( 0 hom. 56 hem. )

Consequence

ADGRG4
NM_153834.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.657

Publications

0 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0125133395).

BP6

Variant X-136344464-C-A is Benign according to our data. Variant chrX-136344464-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3051572.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAdExome4 at 101 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.758C>A	p.Ser253Tyr	missense	Exon 6 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.758C>A	p.Ser253Tyr	missense	Exon 6 of 26	ENSP00000377699.1	Q8IZF6-1
ADGRG4	ENST00000394141.1	TSL:1	c.143C>A	p.Ser48Tyr	missense	Exon 3 of 23	ENSP00000377697.1	Q8IZF6-3
ADGRG4	ENST00000370652.5	TSL:5	c.758C>A	p.Ser253Tyr	missense	Exon 4 of 24	ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

111897

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00148

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000117

AC:

AN:

180241

AF XY:

0.000215

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:

0.0000940

AC:

101

AN:

1074637

Hom.:

Cov.:

AF XY:

0.000163

AC XY:

AN XY:

343129

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25923

American (AMR)

AF:

0.00

AC:

AN:

34989

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19152

East Asian (EAS)

AF:

0.00

AC:

AN:

30105

South Asian (SAS)

AF:

0.00173

AC:

AN:

53235

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40456

Middle Eastern (MID)

AF:

0.000245

AC:

AN:

4076

European-Non Finnish (NFE)

AF:

0.00000243

AC:

AN:

821422

Other (OTH)

AF:

0.000133

AC:

AN:

45279

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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

AF:

0.0000357

AC:

AN:

111897

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34115

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30810

American (AMR)

AF:

0.00

AC:

AN:

10534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00148

AC:

AN:

2710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53118

Other (OTH)

AF:

0.00

AC:

AN:

1504

Age Distribution

Genome 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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000107

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

ADGRG4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.024

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.0

PhyloP100

0.66

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.3

REVEL

Benign

0.013

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.088

Vest4

0.079

MutPred

0.33

Loss of disorder (P = 0.0034)

MVP

0.040

MPC

0.19

ClinPred

0.17

GERP RS

2.6

Varity_R

0.19

gMVP

0.30

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over