16-57655473-C-G

Position:

chr16-57655473-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_201525.4(ADGRG1):c.843C>G(p.Ser281Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,613,186 control chromosomes in the GnomAD database, including 231,092 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 30963 hom., cov: 31)

Exomes 𝑓: 0.52 ( 200129 hom. )

Consequence

ADGRG1
NM_201525.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.57

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 links:

ADGRG1 (HGNC:):

ADGRG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2816151E-6).

BP6

Variant 16-57655473-C-G is Benign according to our data. Variant chr16-57655473-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 137493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-57655473-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG1	NM_201525.4 linkuse as main transcript	c.843C>G	p.Ser281Arg	missense_variant	6/14	ENST00000562631.7	NP_958933.1	Q9Y653-2A0A0S2Z517

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7 linkuse as main transcript	c.843C>G	p.Ser281Arg	missense_variant	6/14	1	NM_201525.4	ENSP00000455351.2		Q9Y653-2

Frequencies

GnomAD3 genomes

AF:

0.620

AC:

94104

AN:

151866

Hom.:

30924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.825

Gnomad AMI

AF:

0.609

Gnomad AMR

AF:

0.649

Gnomad ASJ

AF:

0.514

Gnomad EAS

AF:

0.845

Gnomad SAS

AF:

0.574

Gnomad FIN

AF:

0.602

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.485

Gnomad OTH

AF:

0.580

GnomAD3 exomes

AF:

0.595

AC:

149196

AN:

250900

Hom.:

46729

AF XY:

0.579

AC XY:

78507

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.838

Gnomad AMR exome

AF:

0.744

Gnomad ASJ exome

AF:

0.515

Gnomad EAS exome

AF:

0.855

Gnomad SAS exome

AF:

0.566

Gnomad FIN exome

AF:

0.596

Gnomad NFE exome

AF:

0.489

Gnomad OTH exome

AF:

0.557

GnomAD4 exome

AF:

0.515

AC:

752706

AN:

1461204

Hom.:

200129

Cov.:

AF XY:

0.514

AC XY:

373892

AN XY:

726926

show subpopulations

Gnomad4 AFR exome

AF:

0.838

Gnomad4 AMR exome

AF:

0.737

Gnomad4 ASJ exome

AF:

0.515

Gnomad4 EAS exome

AF:

0.814

Gnomad4 SAS exome

AF:

0.559

Gnomad4 FIN exome

AF:

0.583

Gnomad4 NFE exome

AF:

0.478

Gnomad4 OTH exome

AF:

0.533

GnomAD4 genome

AF:

0.620

AC:

94203

AN:

151982

Hom.:

30963

Cov.:

AF XY:

0.627

AC XY:

46534

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.824

Gnomad4 AMR

AF:

0.649

Gnomad4 ASJ

AF:

0.514

Gnomad4 EAS

AF:

0.844

Gnomad4 SAS

AF:

0.572

Gnomad4 FIN

AF:

0.602

Gnomad4 NFE

AF:

0.485

Gnomad4 OTH

AF:

0.584

Alfa

AF:

0.494

Hom.:

11328

Bravo

AF:

0.637

TwinsUK

AF:

0.481

AC:

1784

ALSPAC

AF:

0.471

AC:

1814

ESP6500AA

AF:

0.824

AC:

3624

ESP6500EA

AF:

0.493

AC:

4241

ExAC

AF:

0.591

AC:

71777

Asia WGS

AF:

0.729

AC:

2535

AN:

3478

EpiCase

AF:

0.488

EpiControl

AF:

0.496

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 07, 2013	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -

Bilateral frontoparietal polymicrogyria

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0060

DANN

Benign

0.20

DEOGEN2

Benign

0.071

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

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0035

LIST_S2

Benign

0.27

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

MetaRNN

Benign

0.0000013

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

MetaSVM

Benign

-0.98

PrimateAI

Benign

0.32

PROVEAN

Benign

0.54

N;N;N;N;.;N;N;N

REVEL

Benign

0.019

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

B;B;B;B;.;B;B;B

Vest4

0.049

MutPred

0.14

Loss of phosphorylation at S281 (P = 0.0193);Loss of phosphorylation at S281 (P = 0.0193);Loss of phosphorylation at S281 (P = 0.0193);Loss of phosphorylation at S281 (P = 0.0193);.;Loss of phosphorylation at S281 (P = 0.0193);Loss of phosphorylation at S281 (P = 0.0193);Loss of phosphorylation at S281 (P = 0.0193);

ClinPred

0.0083

GERP RS

-6.2

Varity_R

0.027

gMVP

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over