19-51573399-G-A

Position:

chr19-51573399-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000262259.7(ZNF175):c.70G>A(p.Glu24Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,612,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ZNF175
ENST00000262259.7 missense, splice_region

Scores

Splicing: ADA: 0.0002389

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.539

Variant links:

Genes affected

ZNF175 (HGNC:12964): (zinc finger protein 175) Enables DNA-binding transcription activator activity, RNA polymerase II-specific; DNA-binding transcription repressor activity, RNA polymerase II-specific; and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II and positive regulation of transcription by RNA polymerase II. Located in cytosol; intermediate filament cytoskeleton; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNF175 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.056174606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF175	NM_007147.4 linkuse as main transcript	c.70G>A	p.Glu24Lys	missense_variant, splice_region_variant	2/5	ENST00000262259.7	NP_009078.1
ZNF175	NR_136208.2 linkuse as main transcript	n.443G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ZNF175	ENST00000545217.5 linkuse as main transcript	c.70G>A	p.Glu24Lys	missense_variant	2/2	1		ENSP00000444424
ZNF175	ENST00000262259.7 linkuse as main transcript	c.70G>A	p.Glu24Lys	missense_variant, splice_region_variant	2/5	1	NM_007147.4	ENSP00000262259	P1
ZNF175	ENST00000436511.2 linkuse as main transcript	c.70G>A	p.Glu24Lys	missense_variant, splice_region_variant	1/4	2		ENSP00000440578
ZNF175	ENST00000596504.1 linkuse as main transcript	c.70G>A	p.Glu24Lys	missense_variant, splice_region_variant	2/3	2		ENSP00000470922

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000602

AC:

AN:

249064

Hom.:

AF XY:

0.0000594

AC XY:

AN XY:

134752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000427

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1460622

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726642

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000360

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

The c.70G>A (p.E24K) alteration is located in exon 2 (coding exon 1) of the ZNF175 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the glutamic acid (E) at amino acid position 24 to be replaced by a lysine (K). 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

0.087

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.0045

.;T;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.35

T;T;T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.055

T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.2

.;L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.0

D;N;.;N

REVEL

Benign

0.047

Sift

Benign

0.052

.;T;.;T

Sift4G

Pathogenic

0.0

D;T;D;T

Polyphen

0.53

.;P;.;.

Vest4

0.16

MutPred

0.38

Gain of methylation at E24 (P = 9e-04);Gain of methylation at E24 (P = 9e-04);Gain of methylation at E24 (P = 9e-04);Gain of methylation at E24 (P = 9e-04);

MVP

0.29

MPC

0.14

ClinPred

0.060

GERP RS

1.9

Varity_R

0.068

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00024

dbscSNV1_RF

Benign

0.0040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over