14-104801934-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001137601.3(ZBTB42):c.737C>T(p.Pro246Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,383,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ZBTB42 NM_001137601.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.41

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040926903).
• BP6: Variant 14-104801934-C-T is Benign according to our data. Variant chr14-104801934-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3192087.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB42	NM_001137601.3	c.737C>T	p.Pro246Leu	missense_variant	1/1	ENST00000342537.8
ZBTB42	NM_001370342.1	c.737C>T	p.Pro246Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB42	ENST00000342537.8	c.737C>T	p.Pro246Leu	missense_variant	1/1		NM_001137601.3	P1
ZBTB42	ENST00000555360.1	c.737C>T	p.Pro246Leu	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000715 AC: 1 AN: 139928 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 75338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000418

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1383272 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 681526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000571

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000281

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.17
Dann	Benign	0.59
DEOGEN2	Benign	0.0037	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.021	N
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.49	N;N
MutationTaster	Benign	0.81	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.38	N;N
REVEL	Benign	0.0060
Sift	Benign	0.33	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0020	B;B
Vest4		0.070
MutPred		0.27		Gain of catalytic residue at P248 (P = 5e-04);Gain of catalytic residue at P248 (P = 5e-04);
MVP		0.030
ClinPred		0.041	T
GERP RS		-7.1
Varity_R		0.031

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1173702414; hg19: chr14-105268271;