chr16-57653985-G-T

Variant names:

• chr16-57653985-G-T
• rs587776624
• NM_201525.4:c.621-1G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_201525.4(ADGRG1):​c.621-1G>T variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: ADGRG1 NM_201525.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.49
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.5, offset of 4, new splice context is: ttctcctccctgccatgcAGttg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-57653985-G-T is Pathogenic according to our data. Variant chr16-57653985-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1517611.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201525.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	NM_201525.4	MANE Select	c.621-1G>T		splice_acceptor intron	N/A	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001145771.3		c.621-1G>T		splice_acceptor intron	N/A	NP_001139243.1	Q9Y653-1
	ADGRG1	NM_001370428.1		c.621-1G>T		splice_acceptor intron	N/A	NP_001357357.1	Q9Y653-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.621-1G>T		splice_acceptor intron	N/A	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.621-1G>T		splice_acceptor intron	N/A	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.621-1G>T		splice_acceptor intron	N/A	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		5.5
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: 5
DS_AL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs587776624; hg19: chr16-57687897;