rs1260128774

Positions:

• chr16-57651439-C-T

Variant summary

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

The ENST00000562631.7(ADGRG1):​c.304C>T​(p.His102Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ADGRG1 ENST00000562631.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.00

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=0.13220751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG1	NM_201525.4	c.304C>T	p.His102Tyr	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.304C>T	p.His102Tyr	missense_variant	3/14	1	NM_201525.4	ENSP00000455351	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251460 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 21, 2017

- -

Bilateral frontoparietal polymicrogyria Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.20	.;.;T;T;T;.;T;.;.;.;.;T;.;.;T;T;.;.;.;.;T;.;.;.;.;.;T;T;.;T;T;T;T;T;T;T;T;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.89	D;.;.;D;D;D;D;D;D;D;D;.;D;.;D;D;D;.;.;.;D;D;D;D;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.13	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	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N;N;N;D;N;N;N;N;D;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.20	T;T;T;T;T;D;D;D;T;D;D;T;T;T;D;D;.;D;T;T;T;D;D;D;D;T;D;D;T;D;D;T;T;D;T;D;D;D;T
Sift4G	Benign	0.33	T;T;T;D;T;D;D;T;T;D;D;T;T;T;D;D;T;D;T;T;T;T;D;D;D;T;D;D;T;D;D;T;T;D;T;T;D;D;T
Polyphen		0.43, 0.31	.;B;B;.;B;.;.;.;.;.;.;.;.;B;.;.;.;.;B;B;.;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.15, 0.17, 0.15, 0.19, 0.16, 0.17, 0.19, 0.16
MutPred		0.42		Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);.;.;Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);.;Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);.;.;.;Gain of methylation at K107 (P = 0.0529);.;.;.;.;Gain of methylation at K107 (P = 0.0529);.;Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);.;Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);
MVP		0.94
ClinPred		0.10	T
GERP RS		3.3
Varity_R		0.036
gMVP		0.50

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: rs1260128774; hg19: chr16-57685351;