rs121908463

Variant names:

• chr16-57656244-T-A
• rs121908463
• NM_201525.4:c.1036T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_201525.4(ADGRG1):​c.1036T>A​(p.Cys346Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000666 in 150,192 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C346C) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.05

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 16-57656244-T-A is Pathogenic according to our data. Variant chr16-57656244-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5830.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG1	NM_201525.4	c.1036T>A	p.Cys346Ser	missense_variant	Exon 8 of 14	ENST00000562631.7	NP_958933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7	c.1036T>A	p.Cys346Ser	missense_variant	Exon 8 of 14	1	NM_201525.4	ENSP00000455351.2

Frequencies

GnomAD3 genomes AF: 0.00000666 AC: 1 AN: 150076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 38

GnomAD4 genome AF: 0.00000666 AC: 1 AN: 150192 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73268

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bilateral frontoparietal polymicrogyria Pathogenic:2

Mar 26, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ADGRG1 c.1036T>A (p.Cys346Ser) results in a non-conservative amino acid change located in the GAIN domain (Chang_2016) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251488 control chromosomes (gnomAD). c.1036T>A has been reported in the literature in individuals affected with Polymicrogyria, Bilateral Frontoparietal, and this variant co-segregated with the disease (Piao_2004). These data indicate that the variant is likely to be associated with disease. At least one publication reports this variant had an impact on protein function (Chang_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27184850, 37178061, 15044805). ClinVar contains an entry for this variant (Variation ID: 5830). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	.;.;T;.;T;.;.;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-9.6	D;D;D;D;.;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D;D
Vest4		0.92
MutPred		0.96		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
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: rs121908463; hg19: chr16-57690156;