chr19-44266956-G-C

Position:

• chr19-44266956-G-C

Variant summary

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

The NM_001207005.2(ZNF233):​c.233G>C​(p.Cys78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZNF233 NM_001207005.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.54

Genes affected

ZNF233 (HGNC:30946): (zinc finger protein 233) Predicted to enable DNA-binding transcription factor 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]

ZNF235 (HGNC:12866): (zinc finger protein 235) This gene product belongs to the zinc finger protein superfamily, members of which are regulatory proteins characterized by nucleic acid-binding zinc finger domains. The encoded protein is a member of the Kruppel family of zinc finger proteins, and contains Kruppel-associated box (KRAB) A and B domains and 15 tandemly arrayed C2H2-type zinc fingers. It is an ortholog of the mouse Zfp93 protein. This gene is located in a cluster of zinc finger genes on 19q13.2. [provided by RefSeq, Jul 2008]

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=0.05905956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF233	NM_001207005.2	c.233G>C	p.Cys78Ser	missense_variant	4/5	ENST00000683810.1	NP_001193934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF233	ENST00000683810.1	c.233G>C	p.Cys78Ser	missense_variant	4/5		NM_001207005.2	ENSP00000507588.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460496 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726658

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Dec 16, 2023

The c.233G>C (p.C78S) alteration is located in exon 4 (coding exon 3) of the ZNF233 gene. This alteration results from a G to C substitution at nucleotide position 233, causing the cysteine (C) at amino acid position 78 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	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.025
DANN	Benign	0.30
DEOGEN2	Benign	0.0011	.;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.075	T;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.059	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.41	.;.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.18	.;.;N;.
REVEL	Benign	0.012
Sift	Benign	0.62	.;.;T;.
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.0020	.;.;B;.
Vest4		0.10
MutPred		0.42		Gain of disorder (P = 0.0211);Gain of disorder (P = 0.0211);Gain of disorder (P = 0.0211);Gain of disorder (P = 0.0211);
MVP		0.040
MPC		0.096
ClinPred		0.025	T
GERP RS		-6.4
Varity_R		0.026
gMVP		0.026

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

LitVar

Other links and lift over

dbSNP: rs373752739; hg19: chr19-44771109;