19-12187339-C-T

Position:

• chr19-12187339-C-T

Variant summary

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

The NM_003437.5(ZNF136):​c.961C>T​(p.Pro321Ser) 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. 14/21 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: -0.189

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035188943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF136	NM_003437.5	c.961C>T	p.Pro321Ser	missense_variant	4/4	ENST00000343979.6
ZNF136	NM_001348014.2	c.865C>T	p.Pro289Ser	missense_variant	5/5
ZNF136	NM_001348013.2	c.763C>T	p.Pro255Ser	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF136	ENST00000343979.6	c.961C>T	p.Pro321Ser	missense_variant	4/4	1	NM_003437.5	P1
ZNF136	ENST00000464860.1	n.2125C>T		non_coding_transcript_exon_variant	3/3	1
ZNF136	ENST00000652580.1	c.865C>T	p.Pro289Ser	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

Oct 17, 2023

The c.961C>T (p.P321S) 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 961, causing the proline (P) at amino acid position 321 to be replaced by a serine (S). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.20
DANN	Benign	0.88
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.000010	N
LIST_S2	Benign	0.062	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.1	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.025
MutPred		0.49		Gain of phosphorylation at P321 (P = 0.0677);
MVP		0.081
MPC		0.21
ClinPred		0.057	T
GERP RS		-1.6
Varity_R		0.032
gMVP		0.017

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: chr19-12298154; COSMIC: COSV105224138; COSMIC: COSV105224138;