rs13338340

chr16-57651371-G-Achr16-57651371-G-C

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.236G>A(p.Arg79Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000818 in 1,614,002 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R79R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.19

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 (MetaRNN=0.0057997406).
• BP6: Variant 16-57651371-G-A is Benign according to our data. Variant chr16-57651371-G-A is described in ClinVar as [Benign]. Clinvar id is 380666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00438 (666/152114) while in subpopulation AFR AF= 0.0154 (641/41502). AF 95% confidence interval is 0.0145. There are 3 homozygotes in gnomad4. There are 315 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG1	NM_201525.4	c.236G>A	p.Arg79Gln	missense_variant	3/14	ENST00000562631.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG1	ENST00000562631.7	c.236G>A	p.Arg79Gln	missense_variant	3/14	1	NM_201525.4	P4

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 151996 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00102 AC: 256 AN: 251472 Hom.: 1 AF XY: 0.000758 AC XY: 103 AN XY: 135912

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000448 AC: 655 AN: 1461888 Hom.: 4 Cov.: 32 AF XY: 0.000395 AC XY: 287 AN XY: 727246

Gnomad4 AFR exome AF: 0.0162

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.00438 AC: 666 AN: 152114 Hom.: 3 Cov.: 31 AF XY: 0.00424 AC XY: 315 AN XY: 74376

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000418

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000572 Hom.: 1

Bravo AF: 0.00532

ESP6500AA AF: 0.0152 AC: 67

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00129 AC: 157

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2019	- -

ADGRG1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 17, 2020

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	0.075
Dann	Benign	0.84
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.0058	T;T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N
PROVEAN	Pathogenic	-5.0	D;D
MVP		0.59
ClinPred		0.0053	T
GERP RS		-9.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs13338340; hg19: chr16-57685283;