8-109553912-C-T

Variant names:

• chr8-109553912-C-T
• rs1821543978
• NM_004215.5:c.131C>T

Variant summary

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

The NM_004215.5(EBAG9):​c.131C>T​(p.Thr44Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,218 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: EBAG9 NM_004215.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25

Genes affected

EBAG9 (HGNC:3123): (estrogen receptor binding site associated antigen 9) This gene was identified as an estrogen-responsive gene. Regulation of transcription by estrogen is mediated by estrogen receptor, which binds to the estrogen-responsive element found in the 5'-flanking region of this gene. The encoded protein is a tumor-associated antigen that is expressed at high frequency in a variety of cancers. Alternate splicing results in multiple transcript variants. A pseudogene of this gene has been defined on chromosome 10. [provided by RefSeq, Jul 2013]

ACMG classification

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
EBAG9	NM_004215.5	c.131C>T	p.Thr44Ile	missense_variant	Exon 3 of 7	ENST00000337573.10	NP_004206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EBAG9	ENST00000337573.10	c.131C>T	p.Thr44Ile	missense_variant	Exon 3 of 7	1	NM_004215.5	ENSP00000337675.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1457218 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724642

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00

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.: 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

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.131C>T (p.T44I) alteration is located in exon 3 (coding exon 2) of the EBAG9 gene. This alteration results from a C to T substitution at nucleotide position 131, causing the threonine (T) at amino acid position 44 to be replaced by an isoleucine (I). 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	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;T;T;T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;.;D;D;D;.
M_CAP	Benign	0.0089	T
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.3	M;M;M;.;M;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.9	N;.;N;N;.;D;N
REVEL	Benign	0.20
Sift	Uncertain	0.0070	D;.;D;D;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.97	D;.;D;.;D;.;.
Vest4		0.93
MutPred		0.36		Loss of glycosylation at T44 (P = 0.0173);Loss of glycosylation at T44 (P = 0.0173);Loss of glycosylation at T44 (P = 0.0173);Loss of glycosylation at T44 (P = 0.0173);Loss of glycosylation at T44 (P = 0.0173);Loss of glycosylation at T44 (P = 0.0173);Loss of glycosylation at T44 (P = 0.0173);
MVP		0.31
MPC		1.0
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.27
gMVP		0.86

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: rs1821543978; hg19: chr8-110566141;