19-56384090-C-T

Variant names:

• chr19-56384090-C-T
• NM_001320371.4:c.1327G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001320371.4(ZNF582):​c.1327G>A​(p.Val443Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,480 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF582 NM_001320371.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.17

Genes affected

ZNF582 (HGNC:26421): (zinc finger protein 582) The protein encoded by this gene is a zing finger protein and putative transcription factor that is highly methylated in cervical cancers. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ENSG00000285996 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032918453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF582	NM_001320371.4	c.1327G>A	p.Val443Ile	missense_variant	Exon 5 of 5	ENST00000586929.6	NP_001307300.2
ZNF582	NM_144690.3	c.1327G>A	p.Val443Ile	missense_variant	Exon 5 of 5		NP_653291.1
ZNF582	XR_007066621.1	n.1500G>A		non_coding_transcript_exon_variant	Exon 5 of 6
ZNF582	XR_430188.4	n.1722G>A		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF582	ENST00000586929.6	c.1327G>A	p.Val443Ile	missense_variant	Exon 5 of 5	1	NM_001320371.4	ENSP00000465619.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459480 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1327G>A (p.V443I) alteration is located in exon 5 (coding exon 4) of the ZNF582 gene. This alteration results from a G to A substitution at nucleotide position 1327, causing the valine (V) at amino acid position 443 to be replaced by an isoleucine (I). 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	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.78
DANN	Benign	0.82
DEOGEN2	Benign	0.013	T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.42	.;T;.
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.033	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.13	N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.10	N;.;.
REVEL	Benign	0.019
Sift	Benign	0.039	D;.;.
Sift4G	Uncertain	0.025	D;D;D
Polyphen		0.0020	B;B;B
Vest4		0.049
MutPred		0.45		Loss of ubiquitination at K448 (P = 0.1062);Loss of ubiquitination at K448 (P = 0.1062);Loss of ubiquitination at K448 (P = 0.1062);
MVP		0.061
MPC		0.12
ClinPred		0.12	T
GERP RS		-9.1
Varity_R		0.037
gMVP		0.029

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-56895459;