19-43966125-G-A

Position:

• chr19-43966125-G-A

Variant summary

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

The ENST00000587682.6(ZNF221):​c.623G>A​(p.Cys208Tyr) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C208S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ZNF221 ENST00000587682.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.22

Genes affected

ZNF221 (HGNC:13014): (zinc finger protein 221) 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, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF221 (HGNC:):

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=0.082124084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF221	NM_001297588.2	c.623G>A	p.Cys208Tyr	missense_variant	5/5	ENST00000587682.6	NP_001284517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF221	ENST00000587682.6	c.623G>A	p.Cys208Tyr	missense_variant	5/5	1	NM_001297588.2	ENSP00000467367.1
ZNF221	ENST00000251269.9	c.623G>A	p.Cys208Tyr	missense_variant	6/6	1		ENSP00000251269.4
ZNF221	ENST00000592350.5	c.623G>A	p.Cys208Tyr	missense_variant	6/6	1		ENSP00000467446.1
ZNF221	ENST00000622072.1	c.623G>A	p.Cys208Tyr	missense_variant	4/4	2		ENSP00000477876.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 84

GnomAD4 genome Cov.: 34

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 15, 2023

The c.623G>A (p.C208Y) alteration is located in exon 6 (coding exon 4) of the ZNF221 gene. This alteration results from a G to A substitution at nucleotide position 623, causing the cysteine (C) at amino acid position 208 to be replaced by a tyrosine (Y). 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	0.25
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.13
DANN	Benign	0.41
DEOGEN2	Benign	0.033	T;T;T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.31	.;.;.;T
M_CAP	Benign	0.00063	T
MetaRNN	Benign	0.082	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.52	N;N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.9	.;D;.;.
REVEL	Benign	0.034
Sift	Benign	0.49	.;T;.;.
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.97	D;D;D;D
Vest4		0.090
MutPred		0.30		Loss of disorder (P = 0.097);Loss of disorder (P = 0.097);Loss of disorder (P = 0.097);Loss of disorder (P = 0.097);
MVP		0.15
MPC		0.13
ClinPred		0.31	T
GERP RS		1.5
Varity_R		0.083

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: chr19-44470277;