rs186479054

chr16-57656000-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201525.4(ADGRG1):c.1017+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,614,018 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (10 hom.)
• Consequence: ADGRG1 NM_201525.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001787
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.441

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 16-57656000-G-A is Benign according to our data. Variant chr16-57656000-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-57656000-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00303 (4436/1461676) while in subpopulation NFE AF= 0.00339 (3775/1111988). AF 95% confidence interval is 0.0033. There are 10 homozygotes in gnomad4_exome. There are 2145 alleles in male gnomad4_exome subpopulation. Median coverage is 39. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG1	NM_201525.4	c.1017+8G>A		splice_region_variant, intron_variant		ENST00000562631.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG1	ENST00000562631.7	c.1017+8G>A		splice_region_variant, intron_variant		1	NM_201525.4	P4

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 297 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00203 AC: 509 AN: 250926 Hom.: 3 AF XY: 0.00204 AC XY: 277 AN XY: 135742

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00775

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00303 AC: 4436 AN: 1461676 Hom.: 10 Cov.: 39 AF XY: 0.00295 AC XY: 2145 AN XY: 727148

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00280

Gnomad4 ASJ exome AF: 0.00834

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00143

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00358

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74506

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00288

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00283 Hom.: 0

Bravo AF: 0.00232

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Bilateral frontoparietal polymicrogyria Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 26, 2021	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

ADGRG1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.68
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
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: rs186479054; hg19: chr16-57689912;