14-104801519-T-C

Position:

• chr14-104801519-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001137601.3(ZBTB42):​c.322T>C​(p.Tyr108His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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)
• Consequence: ZBTB42 NM_001137601.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30959532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB42	NM_001137601.3	c.322T>C	p.Tyr108His	missense_variant	1/1	ENST00000342537.8	NP_001131073.1
ZBTB42	NM_001370342.1	c.322T>C	p.Tyr108His	missense_variant	2/2		NP_001357271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB42	ENST00000342537.8	c.322T>C	p.Tyr108His	missense_variant	1/1	6	NM_001137601.3	ENSP00000409107.2
ZBTB42	ENST00000555360.1	c.322T>C	p.Tyr108His	missense_variant	2/2	1		ENSP00000450673.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 90

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 08, 2024

The c.322T>C (p.Y108H) alteration is located in exon 2 (coding exon 1) of the ZBTB42 gene. This alteration results from a T to C substitution at nucleotide position 322, causing the tyrosine (Y) at amino acid position 108 to be replaced by a histidine (H). 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	Pathogenic	0.92
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.36	.;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.70	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.073	T;T
Sift4G	Benign	0.19	T;T
Polyphen		1.0	D;D
Vest4		0.27
MutPred		0.53		Gain of catalytic residue at D109 (P = 0.0017);Gain of catalytic residue at D109 (P = 0.0017);
MVP		0.19
ClinPred		0.79	D
GERP RS		3.0
Varity_R		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-105267856;