14-104801891-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001137601.3(ZBTB42):c.694G>A(p.Glu232Lys) variant causes a missense change. The variant allele was found at a frequency of 0.845 in 1,548,540 control chromosomes in the GnomAD database, including 565,078 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (47407 hom., cov: 34)
  • Exomes 𝑓: 0.85 (517671 hom.)
• Consequence: ZBTB42 NM_001137601.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.95

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.088913E-7).
• BP6: Variant 14-104801891-G-A is Benign according to our data. Variant chr14-104801891-G-A is described in ClinVar as [Benign]. Clinvar id is 803053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB42	NM_001137601.3	c.694G>A	p.Glu232Lys	missense_variant	1/1	ENST00000342537.8
ZBTB42	NM_001370342.1	c.694G>A	p.Glu232Lys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB42	ENST00000342537.8	c.694G>A	p.Glu232Lys	missense_variant	1/1		NM_001137601.3	P1
ZBTB42	ENST00000555360.1	c.694G>A	p.Glu232Lys	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117702 AN: 152104 Hom.: 47375 Cov.: 34

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.889

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.874

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.898

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.794

GnomAD3 exomes AF: 0.756 AC: 114196 AN: 151048 Hom.: 45636 AF XY: 0.759 AC XY: 61142 AN XY: 80604

Gnomad AFR exome AF: 0.620

Gnomad AMR exome AF: 0.669

Gnomad ASJ exome AF: 0.866

Gnomad EAS exome AF: 0.297

Gnomad SAS exome AF: 0.626

Gnomad FIN exome AF: 0.893

Gnomad NFE exome AF: 0.894

Gnomad OTH exome AF: 0.811

GnomAD4 exome AF: 0.853 AC: 1190811 AN: 1396318 Hom.: 517671 Cov.: 77 AF XY: 0.848 AC XY: 584037 AN XY: 688778

Gnomad4 AFR exome AF: 0.614

Gnomad4 AMR exome AF: 0.682

Gnomad4 ASJ exome AF: 0.863

Gnomad4 EAS exome AF: 0.378

Gnomad4 SAS exome AF: 0.633

Gnomad4 FIN exome AF: 0.892

Gnomad4 NFE exome AF: 0.898

Gnomad4 OTH exome AF: 0.809

GnomAD4 genome AF: 0.774 AC: 117794 AN: 152222 Hom.: 47407 Cov.: 34 AF XY: 0.768 AC XY: 57165 AN XY: 74434

Gnomad4 AFR AF: 0.625

Gnomad4 AMR AF: 0.744

Gnomad4 ASJ AF: 0.874

Gnomad4 EAS AF: 0.312

Gnomad4 SAS AF: 0.583

Gnomad4 FIN AF: 0.898

Gnomad4 NFE AF: 0.893

Gnomad4 OTH AF: 0.791

Alfa AF: 0.862 Hom.: 73474

Bravo AF: 0.757

TwinsUK AF: 0.903 AC: 3347

ALSPAC AF: 0.903 AC: 3481

ESP6500AA AF: 0.624 AC: 864

ESP6500EA AF: 0.901 AC: 2860

ExAC AF: 0.722 AC: 15747

Asia WGS AF: 0.444 AC: 1545 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal congenital contracture syndrome 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	9.1e-7	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.30	P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.52	T;T
Polyphen		0.98	D;D
Vest4		0.057
ClinPred		0.063	T
GERP RS		3.7
Varity_R		0.083

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

LitVar

Other links and lift over

dbSNP: rs4983387; hg19: chr14-105268228; COSMIC: COSV61137253;