rs1376041

chr16-57655971-T-Cchr16-57655971-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_201525.4(ADGRG1):c.996T>C(p.Thr332=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 1,613,752 control chromosomes in the GnomAD database, including 423,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48353 hom., cov: 33)
  • Exomes 𝑓: 0.71 (375041 hom.)
• Consequence: ADGRG1 NM_201525.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.183

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-57655971-T-C is Benign according to our data. Variant chr16-57655971-T-C is described in ClinVar as [Benign]. Clinvar id is 158641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-57655971-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.183 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG1	NM_201525.4	c.996T>C	p.Thr332=	synonymous_variant	7/14	ENST00000562631.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG1	ENST00000562631.7	c.996T>C	p.Thr332=	synonymous_variant	7/14	1	NM_201525.4	P4

Frequencies

GnomAD3 genomes AF: 0.790 AC: 120161 AN: 152112 Hom.: 48301 Cov.: 33

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.773

GnomAD3 exomes AF: 0.759 AC: 190874 AN: 251354 Hom.: 73508 AF XY: 0.745 AC XY: 101190 AN XY: 135868

Gnomad AFR exome AF: 0.951

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.746

Gnomad EAS exome AF: 0.809

Gnomad SAS exome AF: 0.681

Gnomad FIN exome AF: 0.765

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.741

GnomAD4 exome AF: 0.714 AC: 1043920 AN: 1461522 Hom.: 375041 Cov.: 56 AF XY: 0.712 AC XY: 517343 AN XY: 727080

Gnomad4 AFR exome AF: 0.955

Gnomad4 AMR exome AF: 0.889

Gnomad4 ASJ exome AF: 0.740

Gnomad4 EAS exome AF: 0.776

Gnomad4 SAS exome AF: 0.675

Gnomad4 FIN exome AF: 0.760

Gnomad4 NFE exome AF: 0.697

Gnomad4 OTH exome AF: 0.728

GnomAD4 genome AF: 0.790 AC: 120272 AN: 152230 Hom.: 48353 Cov.: 33 AF XY: 0.794 AC XY: 59129 AN XY: 74436

Gnomad4 AFR AF: 0.944

Gnomad4 AMR AF: 0.834

Gnomad4 ASJ AF: 0.735

Gnomad4 EAS AF: 0.796

Gnomad4 SAS AF: 0.681

Gnomad4 FIN AF: 0.782

Gnomad4 NFE AF: 0.698

Gnomad4 OTH AF: 0.771

Alfa AF: 0.726 Hom.: 66302

Bravo AF: 0.806

Asia WGS AF: 0.762 AC: 2648 AN: 3478

EpiCase AF: 0.700

EpiControl AF: 0.710

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Bilateral frontoparietal polymicrogyria Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	9.5
Dann	Benign	0.47

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: rs1376041; hg19: chr16-57689883; COSMIC: COSV65635932; COSMIC: COSV65635932;