1-28691588-C-T

Variant names:

• chr1-28691588-C-T
• NM_001319674.2:c.215C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001319674.2(GMEB1):​c.215C>T​(p.Thr72Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,686 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GMEB1 NM_001319674.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.25
• Publications: 0 publications found

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

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=0.092629075).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMEB1	NM_001319674.2	MANE Select	c.215C>T	p.Thr72Ile	missense	Exon 4 of 10	NP_001306603.1	Q9Y692-2
	GMEB1	NM_006582.4		c.245C>T	p.Thr82Ile	missense	Exon 4 of 10	NP_006573.2
	GMEB1	NM_024482.3		c.215C>T	p.Thr72Ile	missense	Exon 4 of 10	NP_077808.1	Q9Y692-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMEB1	ENST00000373816.6	TSL:2 MANE Select	c.215C>T	p.Thr72Ile	missense	Exon 4 of 10	ENSP00000362922.1	Q9Y692-2
	GMEB1	ENST00000294409.2	TSL:1	c.245C>T	p.Thr82Ile	missense	Exon 4 of 10	ENSP00000294409.2	Q9Y692-1
	GMEB1	ENST00000361872.8	TSL:1	c.215C>T	p.Thr72Ile	missense	Exon 4 of 10	ENSP00000355186.4	Q9Y692-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384686 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 686490

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31608

American (AMR) AF: 0.0000245 AC: 1 AN: 40824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24106

East Asian (EAS) AF: 0.00 AC: 0 AN: 37364

South Asian (SAS) AF: 0.00 AC: 0 AN: 76956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5464

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061340

Other (OTH) AF: 0.00 AC: 0 AN: 56188

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.030
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.055
Sift	Benign	0.14	T
Sift4G	Benign	0.22	T
Polyphen		0.010	B
Vest4		0.090
MutPred		0.37		Loss of disorder (P = 0.0334)
MVP		0.18
MPC		0.17
ClinPred		0.41	T
GERP RS		5.2
Varity_R		0.097
gMVP		0.23
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

hg19: chr1-29018100;