rs563444751

Positions:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The ENST00000562631.7(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. 14/20 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 ENST00000562631.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.02

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in ENST00000562631.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017703712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG1	NM_201525.4	c.249C>G	p.Asp83Glu	missense_variant	3/14	ENST00000562631.7	NP_958933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7	c.249C>G	p.Asp83Glu	missense_variant	3/14	1	NM_201525.4	ENSP00000455351	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;T;T;.;T;.;.;.;.;T;.;.;T;T;.;.;.;.;T;.;.;.;T;.;T;.;.;T;T;.;T;.;T;T;.;T;T;T;T;T;T;T;.
Eigen	Benign	-2.7
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.46	T;T;.;.;T;T;T;T;T;T;T;T;T;.;T;.;T;T;T;.;.;.;T;T;T;T;T;T;.;T;.;.;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.018	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.91	D;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.59	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.063
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;.;.;B;.;.;.;.;.;.;.;.;B;.;.;.;.;B;B;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.036, 0.034, 0.042, 0.067, 0.038, 0.055
MutPred		0.16		.;Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);.;Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);.;.;Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);.;Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);.;.;.;Gain of catalytic residue at D83 (P = 0.0669);.;.;Gain of catalytic residue at D83 (P = 0.0669);.;Gain of catalytic residue at D83 (P = 0.0669);.;.;Gain of catalytic residue at D83 (P = 0.0669);.;Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);.;Gain of catalytic residue at D83 (P = 0.0669);Gain of catalytic residue at D83 (P = 0.0669);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

Publications

LitVar

Other links and lift over

dbSNP: rs563444751; hg19: chr16-57685296;