Genetic Variant NM_001145347.2:c.112C>T (chr19-43598857-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001145347.2(ZNF576):c.112C>T(p.Arg38Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,574,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ZNF576
NM_001145347.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.847

Variant links:

Genes affected

ZNF576 (HGNC:28357): (zinc finger protein 576) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and 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]

ZNF576 links:

SRRM5 (HGNC:37248): (serine/arginine repetitive matrix 5)

SRRM5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26578563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF576	NM_001145347.2 link	c.112C>T	p.Arg38Cys	missense_variant	Exon 3 of 3	ENST00000336564.5	NP_001138819.1	Q9H609A0A024R0T0
ZNF576	NM_024327.2 link	c.112C>T	p.Arg38Cys	missense_variant	Exon 3 of 3		NP_077303.1	Q9H609A0A024R0T0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF576	ENST00000336564.5 link	c.112C>T	p.Arg38Cys	missense_variant	Exon 3 of 3	1	NM_001145347.2	ENSP00000337852.4		Q9H609

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000882

AC:

AN:

226668

Hom.:

AF XY:

0.00000829

AC XY:

AN XY:

120686

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:

0.00

Gnomad FIN exome

AF:

0.0000503

Gnomad NFE exome

AF:

0.00000981

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000169

AC:

AN:

1421856

Hom.:

Cov.:

AF XY:

0.0000228

AC XY:

AN XY:

701232

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000221

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000784

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.112C>T (p.R38C) alteration is located in exon 3 (coding exon 2) of the ZNF576 gene. This alteration results from a C to T substitution at nucleotide position 112, causing the arginine (R) at amino acid position 38 to be replaced by a cysteine (C). 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

0.36

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.061

T;T;T;T;T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.87

.;.;.;.;.;D

M_CAP

Benign

0.070

MetaRNN

Benign

0.27

T;T;T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.97

L;L;L;L;L;L

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.9

D;D;D;D;D;D

REVEL

Benign

0.15

Sift

Uncertain

0.0040

D;D;D;D;D;D

Sift4G

Uncertain

0.014

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.25

MutPred

0.45

Loss of solvent accessibility (P = 0.0146);Loss of solvent accessibility (P = 0.0146);Loss of solvent accessibility (P = 0.0146);Loss of solvent accessibility (P = 0.0146);Loss of solvent accessibility (P = 0.0146);Loss of solvent accessibility (P = 0.0146);

MVP

0.44

MPC

1.6

ClinPred

0.90

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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