16-57661656-C-T

Variant names:

• chr16-57661656-C-T
• rs17240890
• NM_201525.4:c.1665-41C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201525.4(ADGRG1):​c.1665-41C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,591,178 control chromosomes in the GnomAD database, including 27,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1954 hom., cov: 33)
  • Exomes 𝑓: 0.18 (25388 hom.)
• Consequence: ADGRG1 NM_201525.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -4.52
• Publications: 3 publications found

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]

ADGRG1 Gene-Disease associations (from GenCC):

• bilateral frontoparietal polymicrogyria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ENSG00000306939 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-57661656-C-T is Benign according to our data. Variant chr16-57661656-C-T is described in ClinVar as Benign. ClinVar VariationId is 158623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201525.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	NM_201525.4	MANE Select	c.1665-41C>T		intron	N/A	NP_958933.1
	ADGRG1	NM_001145771.3		c.1683-41C>T		intron	N/A	NP_001139243.1
	ADGRG1	NM_001370428.1		c.1683-41C>T		intron	N/A	NP_001357357.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.1665-41C>T		intron	N/A	ENSP00000455351.2
	ADGRG1	ENST00000567835.5	TSL:1	c.1683-41C>T		intron	N/A	ENSP00000456794.1
	ADGRG1	ENST00000388813.9	TSL:1	c.1665-41C>T		intron	N/A	ENSP00000373465.5

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21254 AN: 152142 Hom.: 1951 Cov.: 33

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.154 AC: 32003 AN: 208424 AF XY: 0.156

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.00161

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.182 AC: 261770 AN: 1438918 Hom.: 25388 Cov.: 36 AF XY: 0.182 AC XY: 129645 AN XY: 714252

African (AFR) AF: 0.0317 AC: 1041 AN: 32856

American (AMR) AF: 0.143 AC: 5804 AN: 40688

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 4833 AN: 25690

East Asian (EAS) AF: 0.000963 AC: 37 AN: 38410

South Asian (SAS) AF: 0.121 AC: 10169 AN: 84048

European-Finnish (FIN) AF: 0.179 AC: 9117 AN: 51032

Middle Eastern (MID) AF: 0.206 AC: 1107 AN: 5368

European-Non Finnish (NFE) AF: 0.199 AC: 219530 AN: 1101306

Other (OTH) AF: 0.170 AC: 10132 AN: 59520

GnomAD4 genome AF: 0.140 AC: 21259 AN: 152260 Hom.: 1954 Cov.: 33 AF XY: 0.138 AC XY: 10282 AN XY: 74432

African (AFR) AF: 0.0342 AC: 1422 AN: 41566

American (AMR) AF: 0.165 AC: 2527 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3468

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5188

South Asian (SAS) AF: 0.116 AC: 558 AN: 4822

European-Finnish (FIN) AF: 0.173 AC: 1833 AN: 10586

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13645 AN: 68014

Other (OTH) AF: 0.162 AC: 342 AN: 2106

Alfa AF: 0.120 Hom.: 346

Bravo AF: 0.135

Asia WGS AF: 0.0560 AC: 195 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Bilateral frontoparietal polymicrogyria Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.028
DANN	Benign	0.71
PhyloP100		-4.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17240890; hg19: chr16-57695568;