19-35715168-C-T

Variant names:

• chr19-35715168-C-T
• rs775057642
• NM_014383.3:c.542C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014383.3(ZBTB32):​c.542C>T​(p.Thr181Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ZBTB32 NM_014383.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.06

Genes affected

ZBTB32 (HGNC:16763): (zinc finger and BTB domain containing 32) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific; identical protein binding activity; and sequence-specific double-stranded DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040640146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB32	NM_014383.3	c.542C>T	p.Thr181Met	missense_variant	Exon 3 of 7	ENST00000392197.7	NP_055198.1
ZBTB32	NM_001316902.2	c.6-295C>T		intron_variant	Intron 2 of 6		NP_001303831.1
ZBTB32	NM_001316903.2	c.-86-295C>T		intron_variant	Intron 2 of 5		NP_001303832.1
ZBTB32	XM_017026591.2	c.6-295C>T		intron_variant	Intron 2 of 5		XP_016882080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB32	ENST00000392197.7	c.542C>T	p.Thr181Met	missense_variant	Exon 3 of 7	5	NM_014383.3	ENSP00000376035.1
ZBTB32	ENST00000262630.7	c.542C>T	p.Thr181Met	missense_variant	Exon 2 of 6	1		ENSP00000262630.3
ZBTB32	ENST00000481182.1	n.542C>T		non_coding_transcript_exon_variant	Exon 2 of 4	1		ENSP00000433657.1
ZBTB32	ENST00000426659.6	c.-86-295C>T		intron_variant	Intron 2 of 5	3		ENSP00000466524.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152076 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250516 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461348 Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17 AN XY: 726968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152076 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74274

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.542C>T (p.T181M) alteration is located in exon 2 (coding exon 1) of the ZBTB32 gene. This alteration results from a C to T substitution at nucleotide position 542, causing the threonine (T) at amino acid position 181 to be replaced by a methionine (M). 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	0.17
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.010
DANN	Benign	0.58
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.42	.;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.36	N;N
REVEL	Benign	0.013
Sift	Benign	0.23	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.037	B;B
Vest4		0.054
MutPred		0.30		Gain of loop (P = 0.024);Gain of loop (P = 0.024);
MVP		0.20
MPC		0.38
ClinPred		0.060	T
GERP RS		-9.6
Varity_R		0.014
gMVP		0.096

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: rs775057642; hg19: chr19-36206070;