Genetic Variant GMEB1:p.Ile202Leu (chr1-28702443-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001319674.2(GMEB1):c.604A>C(p.Ile202Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. I202V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GMEB1
NM_001319674.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.83

Publications

0 publications found

Variant links:

Genes affected

GMEB1 (HGNC:4370): (glucocorticoid modulatory element binding protein 1) This gene encodes a member of KDWK gene family which associates with GMEB2 protein. The GMEB1-GMEB2 complex is essential for parvovirus DNA replication. Studies in rat for a similar gene suggest that this gene's role is to modulate the transactivation of the glucocorticoid receptor when it is bound to glucocorticoid response elements. Three alternative spliced transcript variants encoding different isoforms exist. [provided by RefSeq, Feb 2016]

GMEB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.078805596).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319674.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GMEB1	NM_001319674.2	MANE Select	c.604A>C	p.Ile202Leu	missense	Exon 7 of 10	NP_001306603.1	Q9Y692-2
GMEB1	NM_006582.4		c.634A>C	p.Ile212Leu	missense	Exon 7 of 10	NP_006573.2
GMEB1	NM_024482.3		c.604A>C	p.Ile202Leu	missense	Exon 7 of 10	NP_077808.1	Q9Y692-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GMEB1	ENST00000373816.6	TSL:2 MANE Select	c.604A>C	p.Ile202Leu	missense	Exon 7 of 10	ENSP00000362922.1	Q9Y692-2
GMEB1	ENST00000294409.2	TSL:1	c.634A>C	p.Ile212Leu	missense	Exon 7 of 10	ENSP00000294409.2	Q9Y692-1
GMEB1	ENST00000361872.8	TSL:1	c.604A>C	p.Ile202Leu	missense	Exon 7 of 10	ENSP00000355186.4	Q9Y692-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251286

AF XY:

0.00

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461292

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111602

Other (OTH)

AF:

0.00

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.019

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.82

M_CAP

Benign

0.0037

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.92

PhyloP100

1.8

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.080

REVEL

Benign

0.071

Sift

Benign

0.38

Sift4G

Benign

0.47

Polyphen

0.0

Vest4

0.23

MutPred

0.097

Loss of sheet (P = 0.1501)

MVP

0.17

MPC

0.36

ClinPred

0.14

GERP RS

3.1

Varity_R

0.058

gMVP

0.44

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over