rs587783660

Variant names:

• chr16-57653336-G-A
• rs587783660
• NM_201525.4:c.620+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000562631.7(ADGRG1):​c.620+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,456,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADGRG1 ENST00000562631.7 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.50
• Publications: 1 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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-57653336-G-A is Pathogenic according to our data. Variant chr16-57653336-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 158634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000562631.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	NM_201525.4	MANE Select	c.620+1G>A		splice_donor intron	N/A	NP_958933.1
	ADGRG1	NM_001145771.3		c.620+1G>A		splice_donor intron	N/A	NP_001139243.1
	ADGRG1	NM_001370428.1		c.620+1G>A		splice_donor intron	N/A	NP_001357357.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.620+1G>A		splice_donor intron	N/A	ENSP00000455351.2
	ADGRG1	ENST00000567835.5	TSL:1	c.620+1G>A		splice_donor intron	N/A	ENSP00000456794.1
	ADGRG1	ENST00000388813.9	TSL:1	c.620+1G>A		splice_donor intron	N/A	ENSP00000373465.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000826 AC: 2 AN: 242098 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456268 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724708

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111916

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome Cov.: 33

Alfa AF: 0.000262 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Bilateral frontoparietal polymicrogyria (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		4.5
GERP RS		4.4
PromoterAI		-0.15	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587783660; hg19: chr16-57687248; COSMIC: COSV65635282; COSMIC: COSV65635282;