8-109550835-C-T

Variant names:

• chr8-109550835-C-T
• rs369134522
• NM_004215.5:c.11C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004215.5(EBAG9):​c.11C>T​(p.Thr4Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000331 in 1,602,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: EBAG9 NM_004215.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3025096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EBAG9	NM_004215.5	c.11C>T	p.Thr4Ile	missense_variant	Exon 2 of 7	ENST00000337573.10	NP_004206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EBAG9	ENST00000337573.10	c.11C>T	p.Thr4Ile	missense_variant	Exon 2 of 7	1	NM_004215.5	ENSP00000337675.5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000210 AC: 5 AN: 237760 AF XY: 0.00

Gnomad AFR exome AF: 0.0000661

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: 0.0000379

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000352 AC: 51 AN: 1450764 Hom.: 0 Cov.: 29 AF XY: 0.0000319 AC XY: 23 AN XY: 721040

Gnomad4 AFR exome AF: 0.0000302 AC: 1 AN: 33164

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44106

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25844

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39398

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 84764

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52858

Gnomad4 NFE exome AF: 0.0000407 AC: 45 AN: 1105036

Gnomad4 Remaining exome AF: 0.0000836 AC: 5 AN: 59836

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74228

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294447 AN: 0.0000294447

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>T (p.T4I) alteration is located in exon 2 (coding exon 1) of the EBAG9 gene. This alteration results from a C to T substitution at nucleotide position 11, causing the threonine (T) at amino acid position 4 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	Uncertain	0.40
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;T;T;T;.;.
Eigen	Benign	0.049
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D;.;D;D;D;.
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.30	T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.7	L;L;L;.;L;.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N;.;N;N;.;D;N
REVEL	Benign	0.20
Sift	Benign	0.19	T;.;T;T;.;D;T
Sift4G	Benign	0.068	T;D;T;T;T;D;D
Polyphen		0.47	P;.;P;.;P;.;.
Vest4		0.58
MVP		0.23
MPC		0.35
ClinPred		0.24	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.087
gMVP		0.54
Mutation Taster		=63/37	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

Publications

LitVar

Other links and lift over

dbSNP: rs369134522; hg19: chr8-110563064;