Genetic Variant NM_020828.2:c.10G>C (chr19-56539028-G-C) – 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_020828.2(ZFP28):c.10G>C(p.Ala4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000779 in 1,284,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. A4S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

ZFP28
NM_020828.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.187

Publications

0 publications found

Variant links:

Genes affected

ZFP28 (HGNC:17801): (ZFP28 zinc finger protein) Predicted to enable DNA-binding transcription factor 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]

ZFP28 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=0.07135913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP28	NM_020828.2 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 8	ENST00000301318.8	NP_065879.1	Q8NHY6-1
ZFP28	NM_001308440.2 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 7		NP_001295369.1	Q8NHY6-2
ZFP28	XM_011526463.4 link	c.182-597G>C		intron_variant	Intron 1 of 7		XP_011524765.2
ZFP28	XM_011526462.4 link	c.-576G>C		upstream_gene_variant			XP_011524764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZFP28	ENST00000301318.8 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 8	1	NM_020828.2	ENSP00000301318.3	Q8NHY6-1
ZFP28	ENST00000591844.5 link	c.10G>C	p.Ala4Pro	missense_variant	Exon 1 of 7	1		ENSP00000468603.1	Q8NHY6-2
ZFP28	ENST00000589836.1 link	n.-102G>C		upstream_gene_variant		5		ENSP00000465853.1	K7EL00
ZFP28	ENST00000594386.1 link	n.-41G>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.79e-7

AC:

AN:

1284246

Hom.:

Cov.:

AF XY:

0.00000159

AC XY:

AN XY:

627680

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25852

American (AMR)

AF:

0.00

AC:

AN:

20932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19218

East Asian (EAS)

AF:

0.0000310

AC:

AN:

32212

South Asian (SAS)

AF:

0.00

AC:

AN:

64764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30664

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3620

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1033954

Other (OTH)

AF:

0.00

AC:

AN:

53030

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Benign

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

6.9

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.012

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.50

T;T

M_CAP

Benign

0.0025

MetaRNN

Benign

0.071

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.69

N;N

PhyloP100

-0.19

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.55

N;.

REVEL

Benign

0.043

Sift

Benign

0.25

T;.

Sift4G

Benign

0.17

T;T

Polyphen

0.49

P;.

Vest4

0.15

MutPred

0.19

Loss of MoRF binding (P = 0.0659);Loss of MoRF binding (P = 0.0659);

MVP

0.085

MPC

0.24

ClinPred

0.059

GERP RS

-0.95

PromoterAI

0.0072

Neutral

(source)

Varity_R

0.060

gMVP

0.11

Mutation Taster

=97/3

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over