dbSNP rs587783658: ADGRG1:p.His89Asn (chr16-57651400-C-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_201525.4(ADGRG1):c.265C>A(p.His89Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H89Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ADGRG1
NM_201525.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.43

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 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_201525.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-57651400-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 158628.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.41895446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG1	NM_201525.4 link	c.265C>A	p.His89Asn	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.265C>A	p.His89Asn	missense_variant	Exon 3 of 14	1	NM_201525.4	ENSP00000455351.2		Q9Y653-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251474

AF XY:

0.00000736

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727246

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:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

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:

0.00000180

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000438

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

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

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.94

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;D;D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.42

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;T;T;T;T;T

MetaSVM

Benign

-0.72

PhyloP100

3.4

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.9

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

REVEL

Benign

0.15

Sift

Uncertain

0.020

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;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.069

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

Polyphen

0.99, 0.98

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

Vest4

0.49, 0.49, 0.49, 0.49, 0.48, 0.49

MutPred

0.37

Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;.;.;Gain of MoRF binding (P = 0.1028);.;.;.;Gain of MoRF binding (P = 0.1028);.;.;Gain of MoRF binding (P = 0.1028);.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);

MVP

0.97

ClinPred

0.96

GERP RS

5.4

Varity_R

0.15

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over