19-56539058-C-A

Variant names:

• chr19-56539058-C-A
• rs2044166737
• NM_020828.2:c.40C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020828.2(ZFP28):​c.40C>A​(p.Pro14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P14Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZFP28 NM_020828.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.414

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]

ACMG classification

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=0.06353572).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP28	NM_020828.2	c.40C>A	p.Pro14Thr	missense_variant	Exon 1 of 8	ENST00000301318.8	NP_065879.1
ZFP28	NM_001308440.2	c.40C>A	p.Pro14Thr	missense_variant	Exon 1 of 7		NP_001295369.1
ZFP28	XM_011526463.4	c.182-567C>A		intron_variant	Intron 1 of 7		XP_011524765.2
ZFP28	XM_011526462.4	c.-546C>A		upstream_gene_variant			XP_011524764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP28	ENST00000301318.8	c.40C>A	p.Pro14Thr	missense_variant	Exon 1 of 8	1	NM_020828.2	ENSP00000301318.3
ZFP28	ENST00000591844.5	c.40C>A	p.Pro14Thr	missense_variant	Exon 1 of 7	1		ENSP00000468603.1
ZFP28	ENST00000589836.1	n.-72C>A		upstream_gene_variant		5		ENSP00000465853.1
ZFP28	ENST00000594386.1	n.-11C>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40C>A (p.P14T) alteration is located in exon 1 (coding exon 1) of the ZFP28 gene. This alteration results from a C to A substitution at nucleotide position 40, causing the proline (P) at amino acid position 14 to be replaced by a threonine (T). 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	0.071
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.85
DANN	Benign	0.90
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.61	N;.
REVEL	Benign	0.0050
Sift	Benign	0.23	T;.
Sift4G	Benign	0.34	T;D
Polyphen		0.0020	B;.
Vest4		0.076
MutPred		0.21		Gain of phosphorylation at P14 (P = 0.0115);Gain of phosphorylation at P14 (P = 0.0115);
MVP		0.088
MPC		0.20
ClinPred		0.040	T
GERP RS		-4.4
Varity_R		0.033
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2044166737; hg19: chr19-57050427;