NM_032828.4:c.628A>G

Variant names:

• chr19-57859040-A-G
• rs768568016
• NM_032828.4:c.628A>G

Variant summary

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

The NM_032828.4(ZNF587):​c.628A>G​(p.Thr210Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF587 NM_032828.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.486
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066857904).

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.628A>G	p.Thr210Ala	missense	Exon 3 of 3	NP_116217.1	Q96SQ5-1
	ZNF587	NM_001204817.2		c.625A>G	p.Thr209Ala	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.628A>G	p.Thr210Ala	missense	Exon 3 of 3	ENSP00000345479.4	Q96SQ5-1
	ZNF587	ENST00000423137.1	TSL:1	c.625A>G	p.Thr209Ala	missense	Exon 3 of 3	ENSP00000393865.1	Q96SQ5-2
	ZNF814	ENST00000596604.5	TSL:1	c.164-8479T>C		intron	N/A	ENSP00000470328.1	M0QZ64

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250802 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4 AN: 1461530 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727090

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

African (AFR) AF: 0.00 AC: 0 AN: 33434

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: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111774

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

⚠️ 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 Cov.: 27

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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	0.070
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.18
DANN	Benign	0.22
DEOGEN2	Benign	0.0031	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.0029	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.49
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.0090
Sift	Benign	0.25	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.060
MutPred		0.28		Gain of ubiquitination at K209 (P = 0.0543)
MVP		0.32
MPC		0.80
ClinPred		0.52	D
GERP RS		-0.47
Varity_R		0.018
gMVP		0.0037
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: rs768568016; hg19: chr19-58370408;