19-44172874-A-C

Position:

• chr19-44172874-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001032373.2(ZNF226):​c.157A>C​(p.Lys53Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,784 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: 0.0000028 (0 hom.)
• Consequence: ZNF226 NM_001032373.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0120

Genes affected

ZNF226 (HGNC:13019): (zinc finger protein 226) 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10568774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF226	NM_001032373.2	c.157A>C	p.Lys53Gln	missense_variant	5/6	ENST00000337433.10	NP_001027545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF226	ENST00000337433.10	c.157A>C	p.Lys53Gln	missense_variant	5/6	1	NM_001032373.2	ENSP00000336719.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450784 Hom.: 0 Cov.: 30 AF XY: 0.00000555 AC XY: 4 AN XY: 720202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

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

Aug 12, 2021

The c.157A>C (p.K53Q) alteration is located in exon 5 (coding exon 3) of the ZNF226 gene. This alteration results from a A to C substitution at nucleotide position 157, causing the lysine (K) at amino acid position 53 to be replaced by a glutamine (Q). 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	0.073
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.7
DANN	Benign	0.88
DEOGEN2	Benign	0.026	.;.;T;.;.;.;.;.;.;.;.;.;.;.;T;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.0086	T;.;T;T;T;T;.;.;.;T;T;T;T;T;.;.;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	.;.;L;.;.;.;.;L;L;L;.;.;.;.;L;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	.;.;N;.;.;.;.;N;.;N;.;.;.;.;.;N;.
REVEL	Benign	0.0090
Sift	Benign	0.12	.;.;T;.;.;.;.;T;.;T;.;.;.;.;.;T;.
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.015	.;.;B;.;.;.;.;.;.;.;.;.;.;.;B;B;.
Vest4		0.044, 0.085, 0.082, 0.10, 0.10
MutPred		0.44		Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);.;Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);Loss of methylation at K53 (P = 0.0012);
MVP		0.49
MPC		0.019
ClinPred		0.023	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.10

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: rs1555783337; hg19: chr19-44677027;