Genetic Variant ADGRG1:c.-36+151A>T (chr16-57628953-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_201525.4(ADGRG1):c.-36+151A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 585,454 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 26)

Exomes 𝑓: 0.015 ( 17 hom. )

Consequence

ADGRG1
NM_201525.4 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.636

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ADGRG1 links:

ENSG00000261633 (HGNC:):

ENSG00000261633 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

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

BP6

Variant 16-57628953-A-T is Benign according to our data. Variant chr16-57628953-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1254765.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00365 (375/102616) while in subpopulation AFR AF = 0.00827 (203/24536). AF 95% confidence interval is 0.00734. There are 2 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG1	NM_201525.4 link	c.-36+151A>T		intron_variant	Intron 1 of 13	ENST00000562631.7	NP_958933.1	Q9Y653-2A0A0S2Z517

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7 link	c.-36+151A>T		intron_variant	Intron 1 of 13	1	NM_201525.4	ENSP00000455351.2		Q9Y653-2

Frequencies

GnomAD3 genomes

AF:

0.00362

AC:

371

AN:

102548

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00814

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00153

Gnomad ASJ

AF:

0.00672

Gnomad EAS

AF:

0.000992

Gnomad SAS

AF:

0.00448

Gnomad FIN

AF:

0.000667

Gnomad MID

AF:

0.00485

Gnomad NFE

AF:

0.00227

Gnomad OTH

AF:

0.00349

GnomAD4 exome

AF:

0.0146

AC:

7051

AN:

482838

Hom.:

AF XY:

0.0148

AC XY:

3349

AN XY:

225906

show subpopulations

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

African (AFR)

AF:

0.0244

AC:

186

AN:

7614

American (AMR)

AF:

0.00868

AC:

AN:

576

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

AN:

3054

East Asian (EAS)

AF:

0.00340

AC:

AN:

2060

South Asian (SAS)

AF:

0.00902

AC:

AN:

9974

European-Finnish (FIN)

AF:

0.00588

AC:

AN:

170

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

972

European-Non Finnish (NFE)

AF:

0.0146

AC:

6475

AN:

442764

Other (OTH)

AF:

0.0155

AC:

243

AN:

15654

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.386

Heterozygous variant carriers

332

664

995

1327

1659

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

340

680

1020

1360

1700

<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

AF:

0.00365

AC:

375

AN:

102616

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

195

AN XY:

49984

show subpopulations

African (AFR)

AF:

0.00827

AC:

203

AN:

24536

American (AMR)

AF:

0.00153

AC:

AN:

10474

Ashkenazi Jewish (ASJ)

AF:

0.00672

AC:

AN:

2382

East Asian (EAS)

AF:

0.000994

AC:

AN:

3018

South Asian (SAS)

AF:

0.00448

AC:

AN:

3122

European-Finnish (FIN)

AF:

0.000667

AC:

AN:

7496

Middle Eastern (MID)

AF:

0.00521

AC:

AN:

192

European-Non Finnish (NFE)

AF:

0.00227

AC:

112

AN:

49408

Other (OTH)

AF:

0.00347

AC:

AN:

1440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.180

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 24, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.8

(source)

DANN

Benign

0.53

PhyloP100

-0.64

PromoterAI

0.029

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over