rs121908464

Positions:

chr16-57661707-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_201525.4(ADGRG1):c.1675C>T(p.Arg559Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R559Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ADGRG1
NM_201525.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.00

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 16-57661707-C-T is Pathogenic according to our data. Variant chr16-57661707-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-57661707-C-T is described in Lovd as [Pathogenic]. Variant chr16-57661707-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG1	NM_201525.4 linkuse as main transcript	c.1675C>T	p.Arg559Trp	missense_variant	13/14	ENST00000562631.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG1	ENST00000562631.7 linkuse as main transcript	c.1675C>T	p.Arg559Trp	missense_variant	13/14	1	NM_201525.4	P4	Q9Y653-2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000808

AC:

AN:

247534

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133944

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461174

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726866

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000526

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2016	The R565W variant in the GPR56 gene has been reported previously in the homozygous state in multiple children affected with bilateral frontoparietal polymicrogyria (Piao et al., 2004; Piao et al., 2005). Functional studies show that cells transfected with R565W demonstrate a lack of surface expression (Ke et al., 2008; Luo et al., 2014). The R565W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R565W variant is a non-conservative amino acid substitution, which occurs at a position that is not conserved. Therefore, the R565W variant is a strong candidate for a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 565 of the ADGRG1 protein (p.Arg565Trp). This variant is present in population databases (rs121908464, gnomAD 0.008%). This missense change has been observed in individuals with bilateral frontoparietal polymicrogyria (PMID: 15044805, 19016831). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5831). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ADGRG1 protein function. Experimental studies have shown that this missense change affects ADGRG1 function (PMID: 21349848, 24949629, 28424266). For these reasons, this variant has been classified as Pathogenic. -

Bilateral frontoparietal polymicrogyria

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R565W in ADGRG1 (NM_005682.7) has been previously reported in mutliple affected indviduals (Chiang NY et al).Functional studies have shown a damaging effect (Luo R et al). The variant has been submitted to ClinVar as Pathogenic. The p.R565W variant is observed in 1/34,456 (0.0029%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R565W missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1693 in ADGRG1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

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

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.97

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

MetaSVM

Benign

-0.35

MutationTaster

Benign

0.52

A;A;A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.6

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

REVEL

Uncertain

0.34

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.029

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

Polyphen

1.0

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

Vest4

0.80

MutPred

0.87

.;Loss of catalytic residue at R565 (P = 0.1194);Loss of catalytic residue at R565 (P = 0.1194);.;.;.;.;.;

MVP

0.94

ClinPred

0.97

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.70

gMVP

0.51

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