14-104801353-C-G

Variant names:

• chr14-104801353-C-G
• rs753532152
• NM_001137601.3:c.156C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001137601.3(ZBTB42):​c.156C>G​(p.Phe52Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000082 in 1,548,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: ZBTB42 NM_001137601.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.84
• Publications: 0 publications found

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]

ZBTB42 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 6

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001137601.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB42	NM_001137601.3	MANE Select	c.156C>G	p.Phe52Leu	missense	Exon 1 of 1	NP_001131073.1	B2RXF5
	ZBTB42	NM_001370342.1		c.156C>G	p.Phe52Leu	missense	Exon 2 of 2	NP_001357271.1	B2RXF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB42	ENST00000342537.8	TSL:6 MANE Select	c.156C>G	p.Phe52Leu	missense	Exon 1 of 1	ENSP00000409107.2	B2RXF5
	ZBTB42	ENST00000555360.1	TSL:1	c.156C>G	p.Phe52Leu	missense	Exon 2 of 2	ENSP00000450673.1	B2RXF5
	ZBTB42	ENST00000962340.1		c.156C>G	p.Phe52Leu	missense	Exon 2 of 2	ENSP00000632399.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000280 AC: 4 AN: 142896 AF XY: 0.0000260

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000773

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000852 AC: 119 AN: 1395922 Hom.: 0 Cov.: 91 AF XY: 0.0000726 AC XY: 50 AN XY: 688316

African (AFR) AF: 0.00 AC: 0 AN: 31528

American (AMR) AF: 0.00 AC: 0 AN: 35542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25092

East Asian (EAS) AF: 0.00 AC: 0 AN: 35688

South Asian (SAS) AF: 0.00 AC: 0 AN: 79054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.000108 AC: 116 AN: 1077956

Other (OTH) AF: 0.0000518 AC: 3 AN: 57894

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152200 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74358

African (AFR) AF: 0.0000965 AC: 4 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.33	N
PhyloP100		6.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.35
Sift	Benign	0.34	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.47		Gain of catalytic residue at V47 (P = 0.0157)
MVP		0.14
ClinPred		0.49	T
GERP RS		2.9
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs753532152; hg19: chr14-105267690;