Genetic Variant NM_001319674.2:c.230C>T (chr1-28691603-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001319674.2(GMEB1):c.230C>T(p.Ala77Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000064 in 1,407,168 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A77T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

GMEB1
NM_001319674.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

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 made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046244174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMEB1	NM_001319674.2 link	c.230C>T	p.Ala77Val	missense_variant	Exon 4 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.230C>T	p.Ala77Val	missense_variant	Exon 4 of 10	2	NM_001319674.2	ENSP00000362922.1	Q9Y692-2
GMEB1	ENST00000294409.2 link	c.260C>T	p.Ala87Val	missense_variant	Exon 4 of 10	1		ENSP00000294409.2	Q9Y692-1
GMEB1	ENST00000361872.8 link	c.230C>T	p.Ala77Val	missense_variant	Exon 4 of 10	1		ENSP00000355186.4	Q9Y692-2
GMEB1	ENST00000480454.1 link	n.309C>T		non_coding_transcript_exon_variant	Exon 3 of 9	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000292

AC:

AN:

240072

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

130108

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000221

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000640

AC:

AN:

1407168

Hom.:

Cov.:

AF XY:

0.00000571

AC XY:

AN XY:

700022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000211

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.260C>T (p.A87V) alteration is located in exon 4 (coding exon 3) of the GMEB1 gene. This alteration results from a C to T substitution at nucleotide position 260, causing the alanine (A) at amino acid position 87 to be replaced by a valine (V). 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

0.086

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

.;.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.86

.;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.046

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;.;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.24

N;N;N

REVEL

Benign

0.026

Sift

Benign

0.27

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0050

.;.;B

Vest4

0.076

MutPred

0.45

.;.;Gain of catalytic residue at A87 (P = 0.0065);

MVP

0.34

MPC

0.15

ClinPred

0.042

GERP RS

3.3

Varity_R

0.021

gMVP

0.42

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