16-57659696-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201525.4(ADGRG1):c.1555+15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,611,888 control chromosomes in the GnomAD database, including 1,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (143 hom., cov: 32)
  • Exomes 𝑓: 0.013 (1130 hom.)
• Consequence: ADGRG1 NM_201525.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.259

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-57659696-G-C is Benign according to our data. Variant chr16-57659696-G-C is described in ClinVar as [Benign]. Clinvar id is 137496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-57659696-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG1	NM_201525.4	c.1555+15G>C		intron_variant		ENST00000562631.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG1	ENST00000562631.7	c.1555+15G>C		intron_variant		1	NM_201525.4	P4

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2632 AN: 152084 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0354 AC: 8687 AN: 245728 Hom.: 565 AF XY: 0.0348 AC XY: 4655 AN XY: 133770

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.0558

Gnomad ASJ exome AF: 0.00341

Gnomad EAS exome AF: 0.200

Gnomad SAS exome AF: 0.0667

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.0283

GnomAD4 exome AF: 0.0135 AC: 19663 AN: 1459684 Hom.: 1130 Cov.: 35 AF XY: 0.0148 AC XY: 10735 AN XY: 726100

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.0544

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.187

Gnomad4 SAS exome AF: 0.0616

Gnomad4 FIN exome AF: 0.0255

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0174 AC: 2643 AN: 152204 Hom.: 143 Cov.: 32 AF XY: 0.0213 AC XY: 1587 AN XY: 74418

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.0429

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.0739

Gnomad4 FIN AF: 0.0302

Gnomad4 NFE AF: 0.00241

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.00408 Hom.: 2

Bravo AF: 0.0171

Asia WGS AF: 0.145 AC: 505 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Bilateral frontoparietal polymicrogyria Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.8
Dann	Benign	0.34

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: rs75843478; hg19: chr16-57693608; COSMIC: COSV65636385;