Genetic Variant GMEB1:p.Ser49Trp (chr1-28690121-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001319674.2(GMEB1):c.146C>G(p.Ser49Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,384 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S49L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GMEB1
NM_001319674.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.75

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.146C>G	p.Ser49Trp	missense	Exon 3 of 10	NP_001306603.1	Q9Y692-2
GMEB1	NM_006582.4		c.176C>G	p.Ser59Trp	missense	Exon 3 of 10	NP_006573.2
GMEB1	NM_024482.3		c.146C>G	p.Ser49Trp	missense	Exon 3 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.146C>G	p.Ser49Trp	missense	Exon 3 of 10	ENSP00000362922.1	Q9Y692-2
GMEB1	ENST00000294409.2	TSL:1	c.176C>G	p.Ser59Trp	missense	Exon 3 of 10	ENSP00000294409.2	Q9Y692-1
GMEB1	ENST00000361872.8	TSL:1	c.146C>G	p.Ser49Trp	missense	Exon 3 of 10	ENSP00000355186.4	Q9Y692-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451384

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33030

American (AMR)

AF:

0.00

AC:

AN:

43762

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25978

East Asian (EAS)

AF:

0.00

AC:

AN:

39336

South Asian (SAS)

AF:

0.00

AC:

AN:

84402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105934

Other (OTH)

AF:

0.00

AC:

AN:

59932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.69

PhyloP100

3.7

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.20

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.019

Polyphen

0.99

Vest4

0.62

MutPred

0.39

Gain of sheet (P = 4e-04)

MVP

0.35

MPC

0.67

ClinPred

0.86

GERP RS

4.7

Varity_R

0.15

gMVP

0.55

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.30

Position offset: -47

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