Genetic Variant GMEB1:p.Thr231Met (chr1-28702531-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001319674.2(GMEB1):c.692C>T(p.Thr231Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,506 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GMEB1
NM_001319674.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.48

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMEB1	NM_001319674.2 link	c.692C>T	p.Thr231Met	missense_variant	Exon 7 of 10	ENST00000373816.6	NP_001306603.1	Q9Y692-2B1AT47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GMEB1	ENST00000373816.6 link	c.692C>T	p.Thr231Met	missense_variant	Exon 7 of 10	2	NM_001319674.2	ENSP00000362922.1	Q9Y692-2
GMEB1	ENST00000294409.2 link	c.722C>T	p.Thr241Met	missense_variant	Exon 7 of 10	1		ENSP00000294409.2	Q9Y692-1
GMEB1	ENST00000361872.8 link	c.692C>T	p.Thr231Met	missense_variant	Exon 7 of 10	1		ENSP00000355186.4	Q9Y692-2
GMEB1	ENST00000480454.1 link	n.771C>T		non_coding_transcript_exon_variant	Exon 6 of 9	1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251428

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135890

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461484

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.722C>T (p.T241M) alteration is located in exon 7 (coding exon 6) of the GMEB1 gene. This alteration results from a C to T substitution at nucleotide position 722, causing the threonine (T) at amino acid position 241 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.034

.;.;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

.;D;D

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

.;.;L

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.51

N;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.017

D;D;D

Sift4G

Benign

0.20

T;T;T

Polyphen

0.78

.;.;P

Vest4

0.71

MutPred

0.24

.;.;Loss of glycosylation at T241 (P = 0.0474);

MVP

0.46

MPC

0.92

ClinPred

0.47

GERP RS

5.5

Varity_R

0.050

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over