19-42078864-G-T

Position:

• chr19-42078864-G-T

Variant summary

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

The NM_022752.6(ZNF574):​c.258G>T​(p.Met86Ile) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF574 NM_022752.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.582

Genes affected

ZNF574 (HGNC:26166): (zinc finger protein 574) 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 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=0.06695059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF574	NM_022752.6	c.258G>T	p.Met86Ile	missense_variant	2/2	ENST00000359044.5	NP_073589.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF574	ENST00000359044.5	c.258G>T	p.Met86Ile	missense_variant	2/2	1	NM_022752.6	ENSP00000351939.3
ZNF574	ENST00000222339.7	c.528G>T	p.Met176Ile	missense_variant	2/2	3		ENSP00000222339.6
ZNF574	ENST00000600245.1	c.258G>T	p.Met86Ile	missense_variant	2/2	2		ENSP00000469029.1
ZNF574	ENST00000597391.1	c.258G>T	p.Met86Ile	missense_variant	3/3	4		ENSP00000471611.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 28, 2024

The c.258G>T (p.M86I) alteration is located in exon 2 (coding exon 1) of the ZNF574 gene. This alteration results from a G to T substitution at nucleotide position 258, causing the methionine (M) at amino acid position 86 to be replaced by an isoleucine (I). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.013	.;T;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T;.;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.067	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	.;N;.;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.55	N;.;.;N
REVEL	Benign	0.024
Sift	Benign	0.49	T;.;.;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0	.;B;.;B
Vest4		0.26
MutPred		0.34		.;Gain of catalytic residue at L91 (P = 0.0196);Gain of catalytic residue at L91 (P = 0.0196);Gain of catalytic residue at L91 (P = 0.0196);
MVP		0.13
MPC		0.45
ClinPred		0.042	T
GERP RS		2.4
Varity_R		0.089
gMVP		0.098

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: chr19-42583016;