1-28690121-C-T

Variant names:

• chr1-28690121-C-T
• rs544728720
• NM_001319674.2:c.146C>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.146C>T​(p.Ser49Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000156 in 1,602,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GMEB1 NM_001319674.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75
• Publications: 1 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=0.10213125).

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.146C>T	p.Ser49Leu	missense	Exon 3 of 10	NP_001306603.1	Q9Y692-2
	GMEB1	NM_006582.4		c.176C>T	p.Ser59Leu	missense	Exon 3 of 10	NP_006573.2
	GMEB1	NM_024482.3		c.146C>T	p.Ser49Leu	missense	Exon 3 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.146C>T	p.Ser49Leu	missense	Exon 3 of 10	ENSP00000362922.1	Q9Y692-2
	GMEB1	ENST00000294409.2	TSL:1	c.176C>T	p.Ser59Leu	missense	Exon 3 of 10	ENSP00000294409.2	Q9Y692-1
	GMEB1	ENST00000361872.8	TSL:1	c.146C>T	p.Ser49Leu	missense	Exon 3 of 10	ENSP00000355186.4	Q9Y692-2

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150778 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245048 AF XY: 0.0000226

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000152 AC: 22 AN: 1451384 Hom.: 0 Cov.: 28 AF XY: 0.0000180 AC XY: 13 AN XY: 722116

African (AFR) AF: 0.00 AC: 0 AN: 33030

American (AMR) AF: 0.0000229 AC: 1 AN: 43762

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25978

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39336

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1105934

Other (OTH) AF: 0.0000167 AC: 1 AN: 59932

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150846 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73544

African (AFR) AF: 0.0000487 AC: 2 AN: 41034

American (AMR) AF: 0.00 AC: 0 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67898

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

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	0.093
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.051	T
Eigen	Benign	0.0067
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.049
Sift	Benign	0.10	T
Sift4G	Benign	0.35	T
Polyphen		0.52	P
Vest4		0.28
MutPred		0.38		Gain of sheet (P = 4e-04)
MVP		0.17
MPC		0.19
ClinPred		0.58	D
GERP RS		4.7
Varity_R		0.11
gMVP		0.45
Mutation Taster		=70/30	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

dbSNP: rs544728720; hg19: chr1-29016633; COSMIC: COSV99603246; COSMIC: COSV99603246;