Genetic Variant NM_153834.4:c.5371T>C (chrX-136349077-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_153834.4(ADGRG4):c.5371T>C(p.Phe1791Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,094,075 control chromosomes in the GnomAD database, including 82,105 homozygotes. There are 170,593 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 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: 𝑓 0.50 ( 10098 hom., 15741 hem., cov: 22)

Exomes 𝑓: 0.47 ( 82105 hom. 170593 hem. )

Failed GnomAD Quality Control

Consequence

ADGRG4
NM_153834.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.794

Publications

23 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7827749E-4).

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG4	NM_153834.4 link	c.5371T>C	p.Phe1791Leu	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.5371T>C	p.Phe1791Leu	missense_variant	Exon 6 of 26	1	NM_153834.4	ENSP00000377699.1	Q8IZF6-1
ADGRG4	ENST00000394141.1 link	c.4756T>C	p.Phe1586Leu	missense_variant	Exon 3 of 23	1		ENSP00000377697.1	Q8IZF6-3
ADGRG4	ENST00000370652.5 link	c.5371T>C	p.Phe1791Leu	missense_variant	Exon 4 of 24	5		ENSP00000359686.1	Q8IZF6-1

Frequencies

GnomAD3 genomes

AF:

0.499

AC:

54871

AN:

109966

Hom.:

10097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.587

Gnomad AMI

AF:

0.401

Gnomad AMR

AF:

0.475

Gnomad ASJ

AF:

0.489

Gnomad EAS

AF:

0.387

Gnomad SAS

AF:

0.471

Gnomad FIN

AF:

0.410

Gnomad MID

AF:

0.581

Gnomad NFE

AF:

0.472

Gnomad OTH

AF:

0.540

GnomAD2 exomes

AF:

0.462

AC:

82567

AN:

178694

AF XY:

0.466

show subpopulations

Gnomad AFR exome

AF:

0.590

Gnomad AMR exome

AF:

0.407

Gnomad ASJ exome

AF:

0.483

Gnomad EAS exome

AF:

0.382

Gnomad FIN exome

AF:

0.419

Gnomad NFE exome

AF:

0.475

Gnomad OTH exome

AF:

0.481

GnomAD4 exome

AF:

0.472

AC:

516862

AN:

1094075

Hom.:

82105

Cov.:

AF XY:

0.473

AC XY:

170593

AN XY:

360697

show subpopulations

African (AFR)

AF:

0.582

AC:

15280

AN:

26243

American (AMR)

AF:

0.423

AC:

14753

AN:

34857

Ashkenazi Jewish (ASJ)

AF:

0.485

AC:

9317

AN:

19221

East Asian (EAS)

AF:

0.417

AC:

12590

AN:

30187

South Asian (SAS)

AF:

0.469

AC:

25095

AN:

53542

European-Finnish (FIN)

AF:

0.424

AC:

17163

AN:

40452

Middle Eastern (MID)

AF:

0.541

AC:

2222

AN:

4107

European-Non Finnish (NFE)

AF:

0.474

AC:

398285

AN:

839526

Other (OTH)

AF:

0.482

AC:

22157

AN:

45940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

9922

19843

29765

39686

49608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13110

26220

39330

52440

65550

<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

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.499

AC:

54909

AN:

110024

Hom.:

10098

Cov.:

AF XY:

0.486

AC XY:

15741

AN XY:

32372

show subpopulations

African (AFR)

AF:

0.587

AC:

17765

AN:

30264

American (AMR)

AF:

0.475

AC:

4917

AN:

10344

Ashkenazi Jewish (ASJ)

AF:

0.489

AC:

1283

AN:

2622

East Asian (EAS)

AF:

0.387

AC:

1328

AN:

3428

South Asian (SAS)

AF:

0.469

AC:

1225

AN:

2613

European-Finnish (FIN)

AF:

0.410

AC:

2365

AN:

5767

Middle Eastern (MID)

AF:

0.596

AC:

127

AN:

213

European-Non Finnish (NFE)

AF:

0.472

AC:

24814

AN:

52591

Other (OTH)

AF:

0.540

AC:

816

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

989

1979

2968

3958

4947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

516

1032

1548

2064

2580

<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:

0.488

Hom.:

43718

Bravo

AF:

0.508

TwinsUK

AF:

0.471

AC:

1748

ALSPAC

AF:

0.461

AC:

1332

ESP6500AA

AF:

0.589

AC:

2257

ESP6500EA

AF:

0.480

AC:

3229

ExAC

AF:

0.466

AC:

56547

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-1.0

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.034

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.0027

T;T;.

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.24

.;T;T

MetaRNN

Benign

0.00018

T;T;T

MetaSVM

Benign

-0.97

PhyloP100

-0.79

PrimateAI

Benign

0.24

PROVEAN

Benign

1.0

N;N;N

REVEL

Benign

0.0050

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.0040

MutPred

0.083

Gain of glycosylation at T1787 (P = 0.0852);Gain of glycosylation at T1787 (P = 0.0852);.;

MPC

0.038

ClinPred

0.00087

GERP RS

-1.8

Varity_R

0.036

gMVP

0.050

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over