rs1057517931

Positions:

• chr16-57655473-CG-GC
• chr16-57655473-CG-GT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_201525.4(ADGRG1):​c.843_844delinsGC​(p.Ser281_Gly282delinsArgArg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. SG281RW) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.262

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-57655473-CG-GC is Benign according to our data. Variant chr16-57655473-CG-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372698.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRG1	NM_201525.4	c.843_844delinsGC	p.Ser281_Gly282delinsArgArg	missense_variant	6/14	ENST00000562631.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRG1	ENST00000562631.7	c.843_844delinsGC	p.Ser281_Gly282delinsArgArg	missense_variant	6/14	1	NM_201525.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2016

A variant of uncertain significance has been identified in the ADGRG1 gene. The c.843_844delCGinsGC variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.843_844delCGinsGC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.843_844delCGinsGC variant is caused by two nucleotide substitutions (c.843C>G and c.844 G>C) on the same allele (in cis), resulting in an in-frame deletion of a Serine and Glycine residue and the insertion of two Arginine residues, denoted p.Ser281_Gly282delinsArgArg. However, the c.843_844delCGinsGC variant alters residues that are not conserved. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Bilateral frontoparietal polymicrogyria;C3810405:Polymicrogyria, bilateral perisylvian, autosomal recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057517931; hg19: chr16-57689385;