Genetic Variant NM_015428.4:c.100A>G (chr19-50039251-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015428.4(ZNF473):c.100A>G(p.Thr34Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ZNF473
NM_015428.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0120

Publications

0 publications found

Variant links:

Genes affected

ZNF473 (HGNC:23239): (zinc finger protein 473) This gene encodes a member of the Krueppel C2H2-type zinc-finger family of proteins. The encoded protein, a component of the U7 snRNP complex, plays a role in histone 3'-end pre-mRNA processing and may be required for cell cycle progression to S phase. Expression level and methylation status of this gene may be correlated with bone mineral density. [provided by RefSeq, Jul 2016]

ZNF473 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09883678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF473	NM_015428.4 link	c.100A>G	p.Thr34Ala	missense_variant	Exon 3 of 5	ENST00000270617.8	NP_056243.1	Q8WTR7A0A024QZI1
ZNF473	NM_001006656.4 link	c.100A>G	p.Thr34Ala	missense_variant	Exon 3 of 5		NP_001006657.1	Q8WTR7A0A024QZI1
ZNF473	NM_001308424.3 link	c.64A>G	p.Thr22Ala	missense_variant	Exon 2 of 4		NP_001295353.1	Q8WTR7F8WEC7B4DY71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF473	ENST00000270617.8 link	c.100A>G	p.Thr34Ala	missense_variant	Exon 3 of 5	1	NM_015428.4	ENSP00000270617.3		Q8WTR7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111976

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.100A>G (p.T34A) alteration is located in exon 3 (coding exon 2) of the ZNF473 gene. This alteration results from a A to G substitution at nucleotide position 100, causing the threonine (T) at amino acid position 34 to be replaced by an alanine (A). 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

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.0016

.;T;T;T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.44

T;.;.;T;T;T;T

M_CAP

Benign

0.0070

MetaRNN

Benign

0.099

T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

.;L;L;L;.;.;.

PhyloP100

-0.012

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.3

.;.;N;N;N;.;.

REVEL

Benign

0.040

Sift

Benign

0.15

.;.;T;T;T;.;.

Sift4G

Benign

0.27

T;D;D;D;T;T;D

Polyphen

0.021

.;B;B;B;.;.;.

Vest4

0.36, 0.30, 0.29, 0.36, 0.20

MutPred

0.52

Gain of catalytic residue at T34 (P = 0.0196);Gain of catalytic residue at T34 (P = 0.0196);Gain of catalytic residue at T34 (P = 0.0196);Gain of catalytic residue at T34 (P = 0.0196);.;Gain of catalytic residue at T34 (P = 0.0196);Gain of catalytic residue at T34 (P = 0.0196);

MVP

0.21

MPC

0.86

ClinPred

0.067

GERP RS

-0.0022

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.031

gMVP

0.32

Mutation Taster

=98/2

polymorphism

(source)

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

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NM_015428.4:c.100A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over