chr19-56553747-T-C

Variant names:

• chr19-56553747-T-C
• rs138624241
• NM_020828.2:c.962T>C

Variant summary

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

The NM_020828.2(ZFP28):​c.962T>C​(p.Val321Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. V321L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: ZFP28 NM_020828.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.988
• 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]

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.026197761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFP28	NM_020828.2	c.962T>C	p.Val321Ala	missense_variant	Exon 8 of 8	ENST00000301318.8	NP_065879.1
ZFP28	XM_011526463.4	c.935T>C	p.Val312Ala	missense_variant	Exon 8 of 8		XP_011524765.2
ZFP28	XM_011526462.4	c.671T>C	p.Val224Ala	missense_variant	Exon 8 of 8		XP_011524764.1
ZNF470-DT	XM_047439806.1	c.*11-6476A>G		intron_variant	Intron 1 of 1		XP_047295762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZFP28	ENST00000301318.8	c.962T>C	p.Val321Ala	missense_variant	Exon 8 of 8	1	NM_020828.2	ENSP00000301318.3

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251284 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00

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: 0.0000260 AC: 38 AN: 1461792 Hom.: 0 Cov.: 30 AF XY: 0.0000220 AC XY: 16 AN XY: 727198

African (AFR) AF: 0.000597 AC: 20 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111978

Other (OTH) AF: 0.000282 AC: 17 AN: 60384

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74434

African (AFR) AF: 0.000289 AC: 12 AN: 41526

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000520 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.962T>C (p.V321A) alteration is located in exon 8 (coding exon 8) of the ZFP28 gene. This alteration results from a T to C substitution at nucleotide position 962, causing the valine (V) at amino acid position 321 to be replaced by an alanine (A). 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	0.13
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.0
DANN	Benign	0.22
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-0.99
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.010
Sift	Benign	0.25	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.024
MVP		0.088
MPC		0.21
ClinPred		0.43	T
GERP RS		-0.32
Varity_R		0.033
gMVP		0.061
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs138624241; hg19: chr19-57065116;