rs1260128774

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_201525.4(ADGRG1):c.304C>T(p.His102Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ADGRG1
NM_201525.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 0.00

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_201525.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13220751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG1	NM_201525.4 link	c.304C>T	p.His102Tyr	missense_variant	Exon 3 of 14	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.304C>T	p.His102Tyr	missense_variant	Exon 3 of 14	1	NM_201525.4	ENSP00000455351.2		Q9Y653-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251460

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000889

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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

Cov.:

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 21, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bilateral frontoparietal polymicrogyria

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.20

.;.;T;T;T;.;T;.;.;.;.;T;.;.;T;T;.;.;.;.;T;.;.;.;.;.;T;T;.;T;T;T;T;T;T;T;T;T;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.89

D;.;.;D;D;D;D;D;D;D;D;.;D;.;D;D;D;.;.;.;D;D;D;D;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D

M_CAP

Benign

0.039

MetaRNN

Benign

0.13

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.0

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.2

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;N;N;N;N;D;N;N;N;N;D;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.032

Sift

Benign

0.20

T;T;T;T;T;D;D;D;T;D;D;T;T;T;D;D;.;D;T;T;T;D;D;D;D;T;D;D;T;D;D;T;T;D;T;D;D;D;T

Sift4G

Benign

0.33

T;T;T;D;T;D;D;T;T;D;D;T;T;T;D;D;T;D;T;T;T;T;D;D;D;T;D;D;T;D;D;T;T;D;T;T;D;D;T

Polyphen

0.43, 0.31

.;B;B;.;B;.;.;.;.;.;.;.;.;B;.;.;.;.;B;B;.;.;.;.;.;.;.;.;B;.;.;.;.;.;.;.;.;.;.

Vest4

0.15, 0.17, 0.15, 0.19, 0.16, 0.17, 0.19, 0.16

MutPred

0.42

Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);.;.;Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);.;Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);.;.;.;Gain of methylation at K107 (P = 0.0529);.;.;.;.;Gain of methylation at K107 (P = 0.0529);.;Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);.;Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);Gain of methylation at K107 (P = 0.0529);

MVP

0.94

ClinPred

0.10

GERP RS

3.3

Varity_R

0.036

gMVP

0.50

Mutation Taster

=96/4

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over