rs114515505

chr16-57654006-C-Gchr16-57654006-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201525.4(ADGRG1):c.641C>G(p.Ser214Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S214L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.871

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2615654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG1	NM_201525.4	c.641C>G	p.Ser214Trp	missense_variant	5/14	ENST00000562631.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG1	ENST00000562631.7	c.641C>G	p.Ser214Trp	missense_variant	5/14	1	NM_201525.4	P4

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251416 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461772 Hom.: 0 Cov.: 34 AF XY: 0.0000426 AC XY: 31 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000294 Hom.: 1

Bravo AF: 0.000238

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 15, 2022	This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 214 of the ADGRG1 protein (p.Ser214Trp). This variant is present in population databases (rs114515505, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ADGRG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 596586). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2018	- -

Bilateral frontoparietal polymicrogyria Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	0.19
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.57	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.1	N;N;D;N;N;.;N;N;N
Sift	Uncertain	0.026	D;D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.056	T;T;D;T;T;T;T;T;T
Polyphen		0.39	B;D;.;D;B;.;B;B;B
Vest4		0.62
MVP		0.97
ClinPred		0.18	T
GERP RS		4.0
Varity_R		0.089
gMVP		0.51

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: rs114515505; hg19: chr16-57687918;