rs587783653

Positions:

• chr16-57659568-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_201525.4(ADGRG1):​c.1442T>C​(p.Leu481Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.67

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 16-57659568-T-C is Pathogenic according to our data. Variant chr16-57659568-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158619.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG1	NM_201525.4	c.1442T>C	p.Leu481Pro	missense_variant	11/14	ENST00000562631.7	NP_958933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7	c.1442T>C	p.Leu481Pro	missense_variant	11/14	1	NM_201525.4	ENSP00000455351	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bilateral frontoparietal polymicrogyria Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	The homozygous p.Leu487Pro variant in ADGRG1 (also known as GPR56) was identified by our study in 2 siblings with bilateral frontoparietal polymicrogyria. The variant has not been previously reported in individuals with bilateral frontoparietal polymicrogyria and was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 158619) as pathogenic by Genetic Services Laboratory, University of Chicago. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in at least 1 affected homozygotes, and in an individual with bilateral frontoparietal polymicrogyria, increases the likelihood that the variant is pathogenic. In summary, the clinical significance of the p.Leu487Pro variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_supporting (Richards 2015). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ADGRG1 protein function. ClinVar contains an entry for this variant (Variation ID: 158619). This missense change has been observed in individual(s) with frontoparietal polymicrogyria (PMID: 28397838, 29707406). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 487 of the ADGRG1 protein (p.Leu487Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	.;.;T;.;T;.;.;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.9	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.99	D;P;P;D;.;D;D;D
Vest4		0.99
MutPred		0.84		.;Loss of stability (P = 0.0568);Loss of stability (P = 0.0568);.;.;.;.;.;
MVP		0.95
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.90

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: rs587783653; hg19: chr16-57693480;