chr19-12186935-A-G

Position:

• chr19-12186935-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003437.5(ZNF136):​c.557A>G​(p.His186Arg) 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 pathogenic 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: 0.680

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF136	NM_003437.5	c.557A>G	p.His186Arg	missense_variant	4/4	ENST00000343979.6
ZNF136	NM_001348014.2	c.461A>G	p.His154Arg	missense_variant	5/5
ZNF136	NM_001348013.2	c.359A>G	p.His120Arg	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF136	ENST00000343979.6	c.557A>G	p.His186Arg	missense_variant	4/4	1	NM_003437.5	P1
ZNF136	ENST00000464860.1	n.1721A>G		non_coding_transcript_exon_variant	3/3	1
ZNF136	ENST00000652580.1	c.461A>G	p.His154Arg	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 06, 2024

The c.557A>G (p.H186R) alteration is located in exon 4 (coding exon 4) of the ZNF136 gene. This alteration results from a A to G substitution at nucleotide position 557, causing the histidine (H) at amino acid position 186 to be replaced by an arginine (R). 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	0.69
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.00023	N
LIST_S2	Benign	0.047	T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	0.74	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.75		Gain of MoRF binding (P = 0.0245);
MVP		0.84
MPC		0.88
ClinPred		0.98	D
GERP RS		0.95
Varity_R		0.63
gMVP		0.11

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: chr19-12297750;