16-57655473-CG-GT

Variant names:

• chr16-57655473-CG-GT
• rs1057517931
• NM_201525.4:c.843_844delCGinsGT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_201525.4(ADGRG1):​c.843_844delCGinsGT​(p.SerGly281ArgTrp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. SG281RR) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.262
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.843_844delCGinsGT	p.SerGly281ArgTrp	missense	N/A	NP_958933.1
	ADGRG1	NM_001145771.3		c.843_844delCGinsGT	p.SerGly281ArgTrp	missense	N/A	NP_001139243.1
	ADGRG1	NM_001370428.1		c.843_844delCGinsGT	p.SerGly281ArgTrp	missense	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.843_844delCGinsGT	p.SerGly281ArgTrp	missense	N/A	ENSP00000455351.2
	ADGRG1	ENST00000567835.5	TSL:1	c.843_844delCGinsGT	p.SerGly281ArgTrp	missense	N/A	ENSP00000456794.1
	ADGRG1	ENST00000388813.9	TSL:1	c.843_844delCGinsGT	p.SerGly281ArgTrp	missense	N/A	ENSP00000373465.5

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.843_844delinsGT, is a complex sequence change that results in the deletion of 2 and insertion of 2 amino acid(s) in the ADGRG1 protein (p.Ser281_Gly282delinsArgTrp). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with ADGRG1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.26

Splicing

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

Other links and lift over

dbSNP: rs1057517931; hg19: chr16-57689385;