rs17379472

chr16-57659586-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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 same amino acid change has been previously reported as Uncertain significancein 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.95

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a transmembrane_region Helical; Name=3 (size 20) in uniprot entity AGRG1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 [Likely_benign]. Clinvar id is 137495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-57659586-T-C is described in Lovd as [Benign]. Variant chr16-57659586-T-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 88 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG1	NM_201525.4	c.1460T>C	p.Met487Thr	missense_variant	11/14	ENST00000562631.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG1	ENST00000562631.7	c.1460T>C	p.Met487Thr	missense_variant	11/14	1	NM_201525.4	P4

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4286 AN: 152150 Hom.: 88 Cov.: 32

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

GnomAD3 exomes AF: 0.0328 AC: 8240 AN: 251372 Hom.: 200 AF XY: 0.0323 AC XY: 4384 AN XY: 135886

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 SAS exome AF: 0.0157

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.: 35 AF XY: 0.0341 AC XY: 24800 AN XY: 727194

Gnomad4 AFR exome AF: 0.00511

Gnomad4 AMR exome AF: 0.0342

Gnomad4 ASJ exome AF: 0.0153

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0165

Gnomad4 FIN exome AF: 0.0686

Gnomad4 NFE exome AF: 0.0375

Gnomad4 OTH exome AF: 0.0293

GnomAD4 genome AF: 0.0282 AC: 4288 AN: 152268 Hom.: 88 Cov.: 32 AF XY: 0.0294 AC XY: 2186 AN XY: 74444

Gnomad4 AFR AF: 0.00636

Gnomad4 AMR AF: 0.0296

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0727

Gnomad4 NFE AF: 0.0375

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0336 Hom.: 159

Bravo AF: 0.0242

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0387 AC: 149

ESP6500AA AF: 0.00614 AC: 27

ESP6500EA AF: 0.0348 AC: 299

ExAC AF: 0.0319 AC: 3878

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0339

EpiControl AF: 0.0363

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 07, 2013	- -

Bilateral frontoparietal polymicrogyria Benign:2

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. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 26, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	26
Dann	Uncertain	0.99
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0085	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;.;D;D;D
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	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.82

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

Other links and lift over

dbSNP: rs17379472; hg19: chr16-57693498;