chr10-38016985-C-A

Position:

• chr10-38016985-C-A

Variant summary

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

The NM_006954.2(ZNF33A):​c.124C>A​(p.Leu42Met) 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. 12/21 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: ZNF33A NM_006954.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.633

Genes affected

ZNF33A (HGNC:13096): (zinc finger protein 33A) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.33811045).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF33A	NM_006954.2	c.124C>A	p.Leu42Met	missense_variant	3/5	ENST00000432900.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF33A	ENST00000432900.7	c.124C>A	p.Leu42Met	missense_variant	3/5	1	NM_006954.2	A2

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

Jul 25, 2023

The c.124C>A (p.L42M) alteration is located in exon 3 (coding exon 2) of the ZNF33A gene. This alteration results from a C to A substitution at nucleotide position 124, causing the leucine (L) at amino acid position 42 to be replaced by a methionine (M). 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	Benign	0.13
BayesDel_addAF	Benign	0.0079	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T;.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.059	T;T;T;T;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.2	.;.;M;M;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.8	.;.;.;N;N
REVEL	Benign	0.26
Sift	Pathogenic	0.0	.;.;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0, 0.99	.;.;.;D;D
Vest4		0.38
MutPred		0.72		.;.;Gain of phosphorylation at Y45 (P = 0.1168);Gain of phosphorylation at Y45 (P = 0.1168);Gain of phosphorylation at Y45 (P = 0.1168);
MVP		0.43
ClinPred		0.93	D
GERP RS		1.8
Varity_R		0.49
gMVP		0.041

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr10-38305913; COSMIC: COSV100275751;