19-57859061-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 15/21 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. 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
• Publications: 0 publications found

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

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032828.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF587	NM_032828.4	MANE Select	c.649C>T	p.Arg217Cys	missense	Exon 3 of 3	NP_116217.1	Q96SQ5-1
	ZNF587	NM_001204817.2		c.646C>T	p.Arg216Cys	missense	Exon 3 of 3	NP_001191746.1	Q96SQ5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF587	ENST00000339656.8	TSL:1 MANE Select	c.649C>T	p.Arg217Cys	missense	Exon 3 of 3	ENSP00000345479.4	Q96SQ5-1
	ZNF587	ENST00000423137.1	TSL:1	c.646C>T	p.Arg216Cys	missense	Exon 3 of 3	ENSP00000393865.1	Q96SQ5-2
	ZNF814	ENST00000596604.5	TSL:1	c.164-8500G>A		intron	N/A	ENSP00000470328.1	M0QZ64

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

GnomAD2 exomes AF: 0.000180 AC: 45 AN: 249884 AF XY: 0.000192

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33442

American (AMR) AF: 0.0000671 AC: 3 AN: 44712

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

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39698

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86248

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5756

European-Non Finnish (NFE) AF: 0.0000765 AC: 85 AN: 1111720

Other (OTH) AF: 0.000116 AC: 7 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000746 AC: 3 AN: 40210

American (AMR) AF: 0.000332 AC: 5 AN: 15052

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

East Asian (EAS) AF: 0.000788 AC: 4 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000738 AC: 5 AN: 67766

Other (OTH) AF: 0.000972 AC: 2 AN: 2058

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000826783), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000169 Hom.: 0

ExAC AF: 0.000214 AC: 26

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-3.7	N
PhyloP100		-1.8
PrimateAI	Benign	0.20	T
PROVEAN	Benign	5.6	N
REVEL	Benign	0.019
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=97/3	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: rs770671565; hg19: chr19-58370429; COSMIC: COSV57150442; COSMIC: COSV57150442;