chr1-28714238-C-A

Variant names:

• chr1-28714238-C-A
• rs753788875
• NM_001319674.2:c.1157C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001319674.2(GMEB1):​c.1157C>A​(p.Pro386His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GMEB1 NM_001319674.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24464831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMEB1	NM_001319674.2	c.1157C>A	p.Pro386His	missense_variant	Exon 10 of 10	ENST00000373816.6	NP_001306603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMEB1	ENST00000373816.6	c.1157C>A	p.Pro386His	missense_variant	Exon 10 of 10	2	NM_001319674.2	ENSP00000362922.1
GMEB1	ENST00000294409.2	c.1187C>A	p.Pro396His	missense_variant	Exon 10 of 10	1		ENSP00000294409.2
GMEB1	ENST00000361872.8	c.1157C>A	p.Pro386His	missense_variant	Exon 10 of 10	1		ENSP00000355186.4
GMEB1	ENST00000480454.1	n.1236C>A		non_coding_transcript_exon_variant	Exon 9 of 9	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1187C>A (p.P396H) alteration is located in exon 10 (coding exon 9) of the GMEB1 gene. This alteration results from a C to A substitution at nucleotide position 1187, causing the proline (P) at amino acid position 396 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	.;.;T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.6	.;.;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.49	T;T;T
Sift4G	Uncertain	0.032	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.37
MutPred		0.18		.;.;Loss of glycosylation at P396 (P = 0.0167);
MVP		0.28
MPC		0.89
ClinPred		0.89	D
GERP RS		5.9
Varity_R		0.14
gMVP		0.30

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

Other links and lift over

dbSNP: rs753788875; hg19: chr1-29040750;