17-7462605-C-T

Position:

• chr17-7462605-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001128833.2(ZBTB4):​c.2377G>A​(p.Gly793Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000096 in 1,457,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000096 (0 hom.)
• Consequence: ZBTB4 NM_001128833.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24952006).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB4	NM_001128833.2	c.2377G>A	p.Gly793Arg	missense_variant	4/4	ENST00000380599.9	NP_001122305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB4	ENST00000380599.9	c.2377G>A	p.Gly793Arg	missense_variant	4/4	1	NM_001128833.2	ENSP00000369973.4
ZBTB4	ENST00000311403.4	c.2377G>A	p.Gly793Arg	missense_variant	4/4	1		ENSP00000307858.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1457776 Hom.: 0 Cov.: 31 AF XY: 0.00000690 AC XY: 5 AN XY: 724982

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2024

The c.2377G>A (p.G793R) alteration is located in exon 4 (coding exon 2) of the ZBTB4 gene. This alteration results from a G to A substitution at nucleotide position 2377, causing the glycine (G) at amino acid position 793 to be replaced by an arginine (R). 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	0.27
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;T
Eigen	Benign	0.027
Eigen_PC	Benign	0.092
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.085
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.89	P;P
Vest4		0.53
MutPred		0.40		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		0.082
MPC		0.54
ClinPred		0.57	D
GERP RS		4.1
Varity_R		0.096
gMVP		0.44

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: rs34327669; hg19: chr17-7365924;