19-57859061-C-T

Variant names:

• chr19-57859061-C-T
• rs770671565
• NM_032828.4:c.649C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032828.4(ZNF587):​c.649C>T​(p.Arg217Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 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. R217H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 27)
  • Exomes 𝑓: 0.000098 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF587 NM_032828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.81

Genes affected

ZNF587 (HGNC:30955): (zinc finger protein 587) 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]

ZNF814 (HGNC:33258): (zinc finger protein 814) Predicted to enable DNA-binding transcription activator 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]

ENSG00000268750 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015454292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF587	NM_032828.4	c.649C>T	p.Arg217Cys	missense_variant	Exon 3 of 3	ENST00000339656.8	NP_116217.1
ZNF587	NM_001204817.2	c.646C>T	p.Arg216Cys	missense_variant	Exon 3 of 3		NP_001191746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF587	ENST00000339656.8	c.649C>T	p.Arg217Cys	missense_variant	Exon 3 of 3	1	NM_032828.4	ENSP00000345479.4
ENSG00000268750	ENST00000593873.6	c.*291C>T		downstream_gene_variant		4		ENSP00000469133.2

Frequencies

GnomAD3 genomes AF: 0.000127 AC: 19 AN: 150084 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000746

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000332

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000788

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.000972

GnomAD3 exomes AF: 0.000180 AC: 45 AN: 249884 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135316

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00103

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000887

Gnomad OTH exome AF: 0.000329

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000978 AC: 143 AN: 1461492 Hom.: 1 Cov.: 32 AF XY: 0.0000977 AC XY: 71 AN XY: 727060

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000765

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000127 AC: 19 AN: 150084 Hom.: 0 Cov.: 27 AF XY: 0.0000957 AC XY: 7 AN XY: 73170

Gnomad4 AFR AF: 0.0000746

Gnomad4 AMR AF: 0.000332

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000788

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000738

Gnomad4 OTH AF: 0.000972

Alfa AF: 0.000169 Hom.: 0

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.649C>T (p.R217C) alteration is located in exon 3 (coding exon 3) of the ZNF587 gene. This alteration results from a C to T substitution at nucleotide position 649, causing the arginine (R) at amino acid position 217 to be replaced by a cysteine (C). 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	0.079
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.21
DANN	Benign	0.20
DEOGEN2	Benign	0.0021	T;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.00097	N
LIST_S2	Benign	0.20	T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-3.7	N;.;.
PrimateAI	Benign	0.20	T
PROVEAN	Benign	5.6	N;N;N
REVEL	Benign	0.019
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.056
MutPred		0.49		Loss of MoRF binding (P = 0.0089);.;.;
MVP		0.16
MPC		1.9
ClinPred		0.011	T
GERP RS		-2.4
Varity_R		0.026
gMVP		0.0094

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

Publications

LitVar

Other links and lift over

dbSNP: rs770671565; hg19: chr19-58370429; COSMIC: COSV57150442; COSMIC: COSV57150442;