Genetic Variant ADGRG1:c.-36+219C>T (chr16-57629021-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_201525.4(ADGRG1):c.-36+219C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 296,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000068 ( 3 hom., cov: 28)

Exomes 𝑓: 0.000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADGRG1
NM_201525.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.61

Publications

0 publications found

Variant links:

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

ADGRG1 links:

ENSG00000261633 (HGNC:):

ENSG00000261633 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ADGRG1	NM_201525.4	MANE Select	c.-36+219C>T	intron	N/A	NP_958933.1	Q9Y653-2
ADGRG1	NM_001145771.3		c.-154+219C>T	intron	N/A	NP_001139243.1	Q9Y653-1
ADGRG1	NM_001370428.1		c.-154+9140C>T	intron	N/A	NP_001357357.1	Q9Y653-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.-36+219C>T	intron	N/A	ENSP00000455351.2	Q9Y653-2
ADGRG1	ENST00000567835.5	TSL:1	c.-154+8885C>T	intron	N/A	ENSP00000456794.1	Q9Y653-1
ADGRG1	ENST00000388813.9	TSL:1	c.-154+193C>T	intron	N/A	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes

AF:

0.0000677

AC:

AN:

147656

Hom.:

Cov.:

show subpopulations

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:

0.000201

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.000105

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000135

AC:

AN:

296154

Hom.:

AF XY:

0.0000214

AC XY:

AN XY:

140316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

5322

American (AMR)

AF:

0.00

AC:

AN:

340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1738

East Asian (EAS)

AF:

0.00

AC:

AN:

1352

South Asian (SAS)

AF:

0.00

AC:

AN:

5796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

572

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

271186

Other (OTH)

AF:

0.00

AC:

AN:

9754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000677

AC:

AN:

147782

Hom.:

Cov.:

AF XY:

0.0000555

AC XY:

AN XY:

72042

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

39944

American (AMR)

AF:

0.00

AC:

AN:

15020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

5030

South Asian (SAS)

AF:

0.00

AC:

AN:

4628

European-Finnish (FIN)

AF:

0.000201

AC:

AN:

9960

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000105

AC:

AN:

66566

Other (OTH)

AF:

0.00

AC:

AN:

2046

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000482131), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

601

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

6.4

(source)

DANN

Benign

0.71

PhyloP100

-1.6

PromoterAI

-0.0017

Neutral

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over