Genetic Variant NM_015428.4:c.113A>T (chr19-50039264-A-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015428.4(ZNF473):c.113A>T(p.Asn38Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N38T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZNF473
NM_015428.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.49

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF473	NM_015428.4 link	c.113A>T	p.Asn38Ile	missense_variant	Exon 3 of 5	ENST00000270617.8	NP_056243.1	Q8WTR7A0A024QZI1
ZNF473	NM_001006656.4 link	c.113A>T	p.Asn38Ile	missense_variant	Exon 3 of 5		NP_001006657.1	Q8WTR7A0A024QZI1
ZNF473	NM_001308424.3 link	c.77A>T	p.Asn26Ile	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.113A>T	p.Asn38Ile	missense_variant	Exon 3 of 5	1	NM_015428.4	ENSP00000270617.3		Q8WTR7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111946

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

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

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

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

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

.;M;M;M;.;.;.

PhyloP100

1.5

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-6.5

.;.;D;D;D;.;.

REVEL

Benign

0.14

Sift

Uncertain

0.0010

.;.;D;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D

Polyphen

0.13

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

Vest4

0.76, 0.82, 0.81, 0.78, 0.65

MutPred

0.89

Loss of disorder (P = 0.0372);Loss of disorder (P = 0.0372);Loss of disorder (P = 0.0372);Loss of disorder (P = 0.0372);.;Loss of disorder (P = 0.0372);Loss of disorder (P = 0.0372);

MVP

0.47

MPC

0.40

ClinPred

0.82

GERP RS

1.5

Varity_R

0.45

gMVP

0.57

Mutation Taster

=88/12

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.113A>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over