19-56539209-C-A

Variant names:

• chr19-56539209-C-A
• NM_020828.2:c.191C>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.191C>A​(p.Thr64Lys) 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. T64A) 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: -0.0660

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=0.0593642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP28	NM_020828.2	c.191C>A	p.Thr64Lys	missense_variant	Exon 1 of 8	ENST00000301318.8	NP_065879.1
ZFP28	NM_001308440.2	c.191C>A	p.Thr64Lys	missense_variant	Exon 1 of 7		NP_001295369.1
ZFP28	XM_011526463.4	c.182-416C>A		intron_variant	Intron 1 of 7		XP_011524765.2
ZFP28	XM_011526462.4	c.-395C>A		upstream_gene_variant			XP_011524764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP28	ENST00000301318.8	c.191C>A	p.Thr64Lys	missense_variant	Exon 1 of 8	1	NM_020828.2	ENSP00000301318.3
ZFP28	ENST00000591844.5	c.191C>A	p.Thr64Lys	missense_variant	Exon 1 of 7	1		ENSP00000468603.1
ZFP28	ENST00000589836.1	n.80C>A		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000465853.1
ZFP28	ENST00000594386.1	n.141C>A		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191C>A (p.T64K) 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 191, causing the threonine (T) at amino acid position 64 to be replaced by a lysine (K). 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	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.4
DANN	Benign	0.91
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.79	N;.
REVEL	Benign	0.028
Sift	Benign	0.46	T;.
Sift4G	Benign	0.15	T;T
Polyphen		0.20	B;.
Vest4		0.14
MutPred		0.26		Loss of phosphorylation at T64 (P = 0.0223);Loss of phosphorylation at T64 (P = 0.0223);
MVP		0.095
MPC		0.23
ClinPred		0.090	T
GERP RS		-0.62
Varity_R		0.037
gMVP		0.092

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-57050578;