rs121908465

Variant names:

• chr16-57651407-G-C
• rs121908465
• NM_201525.4:c.272G>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_201525.4(ADGRG1):​c.272G>C​(p.Cys91Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 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 (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.95
• Publications: 10 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_201525.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748
• PP5: Variant 16-57651407-G-C is Pathogenic according to our data. Variant chr16-57651407-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG1	NM_201525.4	c.272G>C	p.Cys91Ser	missense_variant	Exon 3 of 14	ENST00000562631.7	NP_958933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7	c.272G>C	p.Cys91Ser	missense_variant	Exon 3 of 14	1	NM_201525.4	ENSP00000455351.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 07, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2 -

Sep 13, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The C91S pathogenic variant in the ADGRG1 gene has been reported previously as a homozygous variant in an individual with bilateral frontoparietal polymicrogyria (BFPP) (Piao et al., 2004). Functional studies suggest that C91S results in reduced or absent ligand binding of the GPR56 protein (Chiang et al., 2011; Luo et al., 2012). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C91S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Therefore, C91S is considered to be a pathogenic variant. -

Bilateral frontoparietal polymicrogyria Pathogenic:1

Mar 26, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.00073	T
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.34	T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.75	D;D
PhyloP100		5.0
PROVEAN	Pathogenic	-5.0	D;D
MVP		0.98
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.29
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908465; hg19: chr16-57685319;