Variant 17-7461988-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001128833.2(ZBTB4):c.2994A>C(p.Glu998Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000555 in 1,441,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ZBTB4
NM_001128833.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.104

Variant links:

Genes affected

ZBTB4 (HGNC:23847): (zinc finger and BTB domain containing 4) Enables several functions, including DNA-binding transcription repressor activity, RNA polymerase II-specific; methyl-CpNpG binding activity; and sequence-specific DNA binding activity. Involved in cellular response to DNA damage stimulus and negative regulation of transcription by RNA polymerase II. Located in cytosol and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

ZBTB4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035785228).

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB4	NM_001128833.2 linkuse as main transcript	c.2994A>C	p.Glu998Asp	missense_variant	4/4	ENST00000380599.9	NP_001122305.1	Q9P1Z0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB4	ENST00000380599.9 linkuse as main transcript	c.2994A>C	p.Glu998Asp	missense_variant	4/4	1	NM_001128833.2	ENSP00000369973.4		Q9P1Z0
ZBTB4	ENST00000311403.4 linkuse as main transcript	c.2994A>C	p.Glu998Asp	missense_variant	4/4	1		ENSP00000307858.4		Q9P1Z0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000424

AC:

AN:

235710

Hom.:

AF XY:

0.00000787

AC XY:

AN XY:

127044

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000939

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000555

AC:

AN:

1441746

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

715276

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000727

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2024

The c.2994A>C (p.E998D) alteration is located in exon 4 (coding exon 2) of the ZBTB4 gene. This alteration results from a A to C substitution at nucleotide position 2994, causing the glutamic acid (E) at amino acid position 998 to be replaced by an aspartic acid (D). 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

0.092

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0052

T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.62

M_CAP

Benign

0.0031

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.062

Sift

Benign

0.20

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0

B;B

Vest4

0.046

MutPred

0.079

Gain of catalytic residue at G997 (P = 0.1263);Gain of catalytic residue at G997 (P = 0.1263);

MVP

0.082

MPC

0.42

ClinPred

0.079

GERP RS

1.6

Varity_R

0.042

gMVP

0.076

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over