rs17379472

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_201525.4(ADGRG1):c.1460T>C(p.Met487Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0341 in 1,614,038 control chromosomes in the GnomAD database, including 1,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M487I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.028 ( 88 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1044 hom. )

Consequence

ADGRG1
NM_201525.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.95

Publications

14 publications found

Variant links:

Genes affected

ADGRG1 (HGNC:4512): (adhesion G protein-coupled receptor G1) This gene encodes a member of the G protein-coupled receptor family and regulates brain cortical patterning. The encoded protein binds specifically to transglutaminase 2, a component of tissue and tumor stroma implicated as an inhibitor of tumor progression. Mutations in this gene are associated with a brain malformation known as bilateral frontoparietal polymicrogyria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ADGRG1 Gene-Disease associations (from GenCC):

bilateral frontoparietal polymicrogyria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ADGRG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_201525.4

BP4

Computational evidence support a benign effect (MetaRNN=0.008508056).

BP6

Variant 16-57659586-T-C is Benign according to our data. Variant chr16-57659586-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0282 (4288/152268) while in subpopulation NFE AF = 0.0375 (2550/68022). AF 95% confidence interval is 0.0363. There are 88 homozygotes in GnomAd4. There are 2186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 88 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG1	NM_201525.4 link	c.1460T>C	p.Met487Thr	missense_variant	Exon 11 of 14	ENST00000562631.7	NP_958933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7 link	c.1460T>C	p.Met487Thr	missense_variant	Exon 11 of 14	1	NM_201525.4	ENSP00000455351.2

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

4286

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00637

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0295

Gnomad ASJ

AF:

0.0164

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0727

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0375

Gnomad OTH

AF:

0.0229

GnomAD2 exomes

AF:

0.0328

AC:

8240

AN:

251372

AF XY:

0.0323

show subpopulations

Gnomad AFR exome

AF:

0.00554

Gnomad AMR exome

AF:

0.0335

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.0736

Gnomad NFE exome

AF:

0.0400

Gnomad OTH exome

AF:

0.0350

GnomAD4 exome

AF:

0.0347

AC:

50760

AN:

1461770

Hom.:

1044

Cov.:

AF XY:

0.0341

AC XY:

24800

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00511

AC:

171

AN:

33480

American (AMR)

AF:

0.0342

AC:

1528

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

401

AN:

26136

East Asian (EAS)

AF:

0.000227

AC:

AN:

39700

South Asian (SAS)

AF:

0.0165

AC:

1421

AN:

86258

European-Finnish (FIN)

AF:

0.0686

AC:

3661

AN:

53390

Middle Eastern (MID)

AF:

0.00954

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0375

AC:

41742

AN:

1111928

Other (OTH)

AF:

0.0293

AC:

1772

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2929

5858

8786

11715

14644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1528

3056

4584

6112

7640

<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:

0.0282

AC:

4288

AN:

152268

Hom.:

Cov.:

AF XY:

0.0294

AC XY:

2186

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00636

AC:

264

AN:

41540

American (AMR)

AF:

0.0296

AC:

453

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0164

AC:

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5174

South Asian (SAS)

AF:

0.0174

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0727

AC:

772

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0375

AC:

2550

AN:

68022

Other (OTH)

AF:

0.0227

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

215

429

644

858

1073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0339

Hom.:

312

Bravo

AF:

0.0242

TwinsUK

AF:

0.0359

AC:

133

ALSPAC

AF:

0.0387

AC:

149

ESP6500AA

AF:

0.00614

AC:

ESP6500EA

AF:

0.0348

AC:

299

ExAC

AF:

0.0319

AC:

3878

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0339

EpiControl

AF:

0.0363

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jan 30, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 20, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 07, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bilateral frontoparietal polymicrogyria

Benign:2

Nov 26, 2019

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

.;T;T;.;.;.;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

.;.;T;.;T;.;.;T

MetaRNN

Benign

0.0085

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.63

PhyloP100

6.0

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.9

D;D;D;D;.;D;D;D

REVEL

Uncertain

0.53

Sift

Benign

0.044

D;D;D;D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

0.93

P;D;D;P;.;P;P;P

Vest4

0.48

ClinPred

0.018

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.82

Mutation Taster

=28/72

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over