rs563444751

Variant names:

• chr16-57651384-C-G
• rs563444751
• NM_201525.4:c.249C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-57651384-C-G
• chr16-57651384-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_201525.4(ADGRG1):​c.249C>G​(p.Asp83Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D83D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.02
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen

ACMG classification

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

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_201525.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017703712).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	NM_201525.4	MANE Select	c.249C>G	p.Asp83Glu	missense	Exon 3 of 14	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001145771.3		c.249C>G	p.Asp83Glu	missense	Exon 4 of 15	NP_001139243.1	Q9Y653-1
	ADGRG1	NM_001370428.1		c.249C>G	p.Asp83Glu	missense	Exon 4 of 15	NP_001357357.1	Q9Y653-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.249C>G	p.Asp83Glu	missense	Exon 3 of 14	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.249C>G	p.Asp83Glu	missense	Exon 4 of 15	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.249C>G	p.Asp83Glu	missense	Exon 4 of 15	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.0040
DANN	Benign	0.27
DEOGEN2	Benign	0.078	T
Eigen	Benign	-2.7
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.93	T
PhyloP100		-4.0
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.063
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MutPred		0.16		Gain of catalytic residue at D83 (P = 0.0669)
MVP		0.67
ClinPred		0.015	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.023
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs563444751; hg19: chr16-57685296;