Genetic Variant NM_201525.4:c.112C>T (chr16-57651247-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP5

The NM_201525.4(ADGRG1):c.112C>T(p.Arg38Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ADGRG1
NM_201525.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 0.106

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-57651248-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 862927.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 16-57651247-C-T is Pathogenic according to our data. Variant chr16-57651247-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 5829.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}. Variant chr16-57651247-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG1	NM_201525.4 link	c.112C>T	p.Arg38Trp	missense_variant	Exon 3 of 14	ENST00000562631.7	NP_958933.1	Q9Y653-2A0A0S2Z517

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7 link	c.112C>T	p.Arg38Trp	missense_variant	Exon 3 of 14	1	NM_201525.4	ENSP00000455351.2		Q9Y653-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251474

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135920

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727222

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000474

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Bilateral frontoparietal polymicrogyria

Pathogenic:2

Jul 24, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ADGRG1 c.112C>T (p.Arg38Trp) results in a non-conservative amino acid change located in the PTX/LNS-Like (PLL) domain (IPR040679) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251474 control chromosomes. c.112C>T has been reported in the literature in multiple homozygous individuals affected with Polymicrogyria, Bilateral Frontoparietal (e.g. Piao_2004, Piao_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolished ligand binding ability in HEK293T cells (Luo_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22238662, 16240336, 15044805). ClinVar contains an entry for this variant (Variation ID: 5829). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 26, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Abnormality of the nervous system

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Dec 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 38 of the ADGRG1 protein (p.Arg38Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with bilateral frontoparietal polymicrogyria (PMID: 15044805, 16240336). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5829). 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, 22238662). This variant disrupts the p.Arg38 amino acid residue in ADGRG1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16240336, 17576745, 22238662, 23981349, 25922261). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Uncertain:1

Sep 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112C>T (p.R38W) alteration is located in exon 4 (coding exon 2) of the ADGRG1 gene. This alteration results from a C to T substitution at nucleotide position 112, causing the arginine (R) at amino acid position 38 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Benign

0.84

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.63

M_CAP

Pathogenic

0.50

MetaRNN

Uncertain

0.66

D;D

PROVEAN

Uncertain

-4.0

D;D

MVP

0.99

ClinPred

0.92

GERP RS

0.55

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