NM_020828.2:c.686C>T

Variant names:

• chr19-56549120-C-T
• rs776198048
• NM_020828.2:c.686C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020828.2(ZFP28):​c.686C>T​(p.Pro229Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000883 in 1,597,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: ZFP28 NM_020828.2 missense, splice_region
• Scores: Splicing: ADA: 0.00009985
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.413

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]

ZNF470-DT (HGNC:55272): (ZNF470 divergent transcript)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045410275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP28	NM_020828.2	c.686C>T	p.Pro229Leu	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000301318.8	NP_065879.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP28	ENST00000301318.8	c.686C>T	p.Pro229Leu	missense_variant, splice_region_variant	Exon 5 of 8	1	NM_020828.2	ENSP00000301318.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000503 AC: 12 AN: 238668 AF XY: 0.0000310

Gnomad AFR exome AF: 0.0000630

Gnomad AMR exome AF: 0.0000320

Gnomad ASJ exome AF: 0.000213

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.0000547

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.0000948 AC: 137 AN: 1445180 Hom.: 0 Cov.: 32 AF XY: 0.0000948 AC XY: 68 AN XY: 717424

African (AFR) AF: 0.0000304 AC: 1 AN: 32896

American (AMR) AF: 0.0000237 AC: 1 AN: 42194

Ashkenazi Jewish (ASJ) AF: 0.000313 AC: 8 AN: 25520

East Asian (EAS) AF: 0.00 AC: 0 AN: 39140

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82876

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.000106 AC: 117 AN: 1103962

Other (OTH) AF: 0.000117 AC: 7 AN: 59710

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152104 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74296

African (AFR) AF: 0.0000242 AC: 1 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.000166

EpiControl AF: 0.0000602

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.686C>T (p.P229L) alteration is located in exon 5 (coding exon 5) of the ZFP28 gene. This alteration results from a C to T substitution at nucleotide position 686, causing the proline (P) at amino acid position 229 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.63	N;N
PhyloP100		-0.41
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.015
Sift	Benign	0.17	T;.
Sift4G	Benign	0.31	T;T
Polyphen		0.057	B;.
Vest4		0.17
MutPred		0.36		Gain of loop (P = 0.0851);Gain of loop (P = 0.0851);
MVP		0.13
MPC		0.18
ClinPred		0.029	T
GERP RS		-1.4
Varity_R		0.040
gMVP		0.14
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.044
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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs776198048; hg19: chr19-57060489; COSMIC: COSV56737193; COSMIC: COSV56737193;