19-44175521-A-T

Variant names:

• chr19-44175521-A-T
• NM_001032373.2:c.259A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001032373.2(ZNF226):​c.259A>T​(p.Ile87Phe) 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. 16/22 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: ZNF226 NM_001032373.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.509
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041431516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF226	NM_001032373.2	c.259A>T	p.Ile87Phe	missense_variant	Exon 6 of 6	ENST00000337433.10	NP_001027545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF226	ENST00000337433.10	c.259A>T	p.Ile87Phe	missense_variant	Exon 6 of 6	1	NM_001032373.2	ENSP00000336719.5

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

May 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.259A>T (p.I87F) alteration is located in exon 6 (coding exon 4) of the ZNF226 gene. This alteration results from a A to T substitution at nucleotide position 259, causing the isoleucine (I) at amino acid position 87 to be replaced by a phenylalanine (F). 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	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.7
DANN	Benign	0.72
DEOGEN2	Benign	0.0094	.;T;.;.;.;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.24	T;T;T;T;T;.;.;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.041	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	.;N;.;.;.;N;N;.
PhyloP100		0.51
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.14	.;N;.;.;.;.;N;.
REVEL	Benign	0.0030
Sift	Benign	0.069	.;T;.;.;.;.;T;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D
Polyphen		0.0010	.;B;.;.;.;B;B;.
Vest4		0.077, 0.083
MutPred		0.27		Loss of MoRF binding (P = 0.1154);Loss of MoRF binding (P = 0.1154);Loss of MoRF binding (P = 0.1154);.;Loss of MoRF binding (P = 0.1154);Loss of MoRF binding (P = 0.1154);Loss of MoRF binding (P = 0.1154);Loss of MoRF binding (P = 0.1154);
MVP		0.17
MPC		0.021
ClinPred		0.031	T
GERP RS		0.31
Varity_R		0.042
gMVP		0.027
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

hg19: chr19-44679674;