rs74326170

Positions:

• chr16-57657497-G-A

Variant summary

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

The ENST00000562631.7(ADGRG1):​c.1286+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,604,548 control chromosomes in the GnomAD database, including 1,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (524 hom., cov: 32)
  • Exomes 𝑓: 0.012 (694 hom.)
• Consequence: ADGRG1 ENST00000562631.7 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0003660
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.224

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=-0.75).
• BP6: Variant 16-57657497-G-A is Benign according to our data. Variant chr16-57657497-G-A is described in ClinVar as [Benign]. Clinvar id is 137494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-57657497-G-A is described in Lovd as [Benign]. Variant chr16-57657497-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG1	NM_201525.4	c.1286+6G>A		splice_donor_region_variant, intron_variant		ENST00000562631.7	NP_958933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7	c.1286+6G>A		splice_donor_region_variant, intron_variant		1	NM_201525.4	ENSP00000455351	P4

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7831 AN: 152138 Hom.: 520 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0863

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.0526

GnomAD3 exomes AF: 0.0246 AC: 6172 AN: 251082 Hom.: 306 AF XY: 0.0219 AC XY: 2978 AN XY: 135726

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.0894

Gnomad SAS exome AF: 0.0165

Gnomad FIN exome AF: 0.000328

Gnomad NFE exome AF: 0.00585

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0123 AC: 17871 AN: 1452292 Hom.: 694 Cov.: 29 AF XY: 0.0120 AC XY: 8670 AN XY: 722976

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.0176

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.0709

Gnomad4 SAS exome AF: 0.0170

Gnomad4 FIN exome AF: 0.000642

Gnomad4 NFE exome AF: 0.00480

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0516 AC: 7859 AN: 152256 Hom.: 524 Cov.: 32 AF XY: 0.0506 AC XY: 3766 AN XY: 74450

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.0227

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.0859

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00575

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0233 Hom.: 136

Bravo AF: 0.0595

Asia WGS AF: 0.0610 AC: 213 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00765

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 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:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Bilateral frontoparietal polymicrogyria Benign:2

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00037
dbscSNV1_RF	Benign	0.040
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: rs74326170; hg19: chr16-57691409;