14-104801808-C-A

Position:

• chr14-104801808-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001137601.3(ZBTB42):​c.611C>A​(p.Pro204Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000286 in 1,397,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ZBTB42 NM_001137601.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.21

Genes affected

ZBTB42 (HGNC:32550): (zinc finger and BTB domain containing 42) The protein encoded by this gene is a member of the C2H2 zinc finger protein family. This protein is predicted to have a pox virus and zinc finger (POZ) domain at the N-terminus and four zinc finger domains at the C-terminus. In human and mouse, the protein localizes to the nuclei of skeletal muscle cells. Knockdown of this gene in zebrafish results in abnormal skeletal muscle development and myofibrillar disorganization. A novel homozygous variant of the human gene has been associated with lethal congenital contracture syndrome, an autosomal recessive disorder that results in muscle wasting. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16952148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB42	NM_001137601.3	c.611C>A	p.Pro204Gln	missense_variant	1/1	ENST00000342537.8	NP_001131073.1
ZBTB42	NM_001370342.1	c.611C>A	p.Pro204Gln	missense_variant	2/2		NP_001357271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB42	ENST00000342537.8	c.611C>A	p.Pro204Gln	missense_variant	1/1	6	NM_001137601.3	ENSP00000409107.2
ZBTB42	ENST00000555360.1	c.611C>A	p.Pro204Gln	missense_variant	2/2	1		ENSP00000450673.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1397676 Hom.: 0 Cov.: 84 AF XY: 0.00000435 AC XY: 3 AN XY: 689308

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: 0.00000371

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

Oct 19, 2024

The c.611C>A (p.P204Q) alteration is located in exon 2 (coding exon 1) of the ZBTB42 gene. This alteration results from a C to A substitution at nucleotide position 611, causing the proline (P) at amino acid position 204 to be replaced by a glutamine (Q). 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	0.20
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0086	T;T
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.094
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.47	.;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.13
Sift	Benign	0.31	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.97	D;D
Vest4		0.12
MutPred		0.35		Gain of catalytic residue at L207 (P = 0.0165);Gain of catalytic residue at L207 (P = 0.0165);
MVP		0.081
ClinPred		0.79	D
GERP RS		3.5
Varity_R		0.10

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: rs749586716; hg19: chr14-105268145;