19-12187382-C-T

Position:

• chr19-12187382-C-T

Variant summary

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

The NM_003437.5(ZNF136):​c.1004C>T​(p.Pro335Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF136 NM_003437.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

Genes affected

ZNF136 (HGNC:12920): (zinc finger protein 136) This gene encodes a zinc finger protein containing a Kruppel-associated box (KRAB) A-box domain at its N-terminus, followed by fourteen contiguous C2H2 zinc finger domains and a degenerate zinc finger. The KRAB A-box showed weak transcriptional repressor activity in a reporter gene assay. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

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=0.40948385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF136	NM_003437.5	c.1004C>T	p.Pro335Leu	missense_variant	4/4	ENST00000343979.6
ZNF136	NM_001348014.2	c.908C>T	p.Pro303Leu	missense_variant	5/5
ZNF136	NM_001348013.2	c.806C>T	p.Pro269Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF136	ENST00000343979.6	c.1004C>T	p.Pro335Leu	missense_variant	4/4	1	NM_003437.5	P1
ZNF136	ENST00000464860.1	n.2168C>T		non_coding_transcript_exon_variant	3/3	1
ZNF136	ENST00000652580.1	c.908C>T	p.Pro303Leu	missense_variant	5/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 17, 2022

The c.1004C>T (p.P335L) alteration is located in exon 4 (coding exon 4) of the ZNF136 gene. This alteration results from a C to T substitution at nucleotide position 1004, causing the proline (P) at amino acid position 335 to be replaced by a leucine (L). 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	0.82
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.00051	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Benign	0.23
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.12
MutPred		0.69		Loss of disorder (P = 0.0362);
MVP		0.55
MPC		0.81
ClinPred		0.92	D
GERP RS		1.4
Varity_R		0.18
gMVP		0.024

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-12298197;