chr19-56539026-G-T

Variant names:

• chr19-56539026-G-T
• rs759247090
• NM_020828.2:c.8G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020828.2(ZFP28):​c.8G>T​(p.Gly3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000262 in 1,434,520 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ZFP28 NM_020828.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.190
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00637874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP28	NM_020828.2	c.8G>T	p.Gly3Val	missense_variant	Exon 1 of 8	ENST00000301318.8	NP_065879.1
ZFP28	NM_001308440.2	c.8G>T	p.Gly3Val	missense_variant	Exon 1 of 7		NP_001295369.1
ZFP28	XM_011526463.4	c.182-599G>T		intron_variant	Intron 1 of 7		XP_011524765.2
ZFP28	XM_011526462.4	c.-578G>T		upstream_gene_variant			XP_011524764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP28	ENST00000301318.8	c.8G>T	p.Gly3Val	missense_variant	Exon 1 of 8	1	NM_020828.2	ENSP00000301318.3
ZFP28	ENST00000591844.5	c.8G>T	p.Gly3Val	missense_variant	Exon 1 of 7	1		ENSP00000468603.1
ZFP28	ENST00000589836.1	n.-104G>T		upstream_gene_variant		5		ENSP00000465853.1
ZFP28	ENST00000594386.1	n.-43G>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 151560 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00443

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000224 AC: 12 AN: 53510 AF XY: 0.000169

Gnomad AFR exome AF: 0.00580

Gnomad AMR exome AF: 0.0000941

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000147 AC: 188 AN: 1282852 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 93 AN XY: 626754

African (AFR) AF: 0.00643 AC: 166 AN: 25832

American (AMR) AF: 0.000192 AC: 4 AN: 20880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19102

East Asian (EAS) AF: 0.00 AC: 0 AN: 32188

South Asian (SAS) AF: 0.00 AC: 0 AN: 64432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30612

Middle Eastern (MID) AF: 0.000277 AC: 1 AN: 3606

European-Non Finnish (NFE) AF: 0.00000290 AC: 3 AN: 1033218

Other (OTH) AF: 0.000264 AC: 14 AN: 52982

GnomAD4 genome AF: 0.00124 AC: 188 AN: 151668 Hom.: 1 Cov.: 30 AF XY: 0.00135 AC XY: 100 AN XY: 74106

African (AFR) AF: 0.00445 AC: 184 AN: 41384

American (AMR) AF: 0.000131 AC: 2 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67804

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000614 Hom.: 0

Bravo AF: 0.00152

ExAC AF: 0.000100 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8G>T (p.G3V) alteration is located in exon 1 (coding exon 1) of the ZFP28 gene. This alteration results from a G to T substitution at nucleotide position 8, causing the glycine (G) at amino acid position 3 to be replaced by a valine (V). 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	0.17
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L;L
PhyloP100		0.19
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.010	B;.
Vest4		0.27
MutPred		0.21		Loss of methylation at R2 (P = 0.182);Loss of methylation at R2 (P = 0.182);
MVP		0.26
MPC		0.81
ClinPred		0.098	T
GERP RS		1.1
PromoterAI		0.070	Neutral
Varity_R		0.21
gMVP		0.080
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs759247090; hg19: chr19-57050395;