chr19-12133119-C-T

Position:

• chr19-12133119-C-T

Variant summary

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

The ENST00000334213.10(ZNF20):​c.1067G>A​(p.Arg356Lys) 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 1,461,858 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R356S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF20 ENST00000334213.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -10.9

Genes affected

ZNF20 (HGNC:12992): (zinc finger protein 20) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF625-ZNF20 (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=0.05389726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF20	NM_021143.4	c.1067G>A	p.Arg356Lys	missense_variant	4/4	ENST00000334213.10	NP_066966.2
ZNF625-ZNF20	NR_037802.1	n.1649G>A		non_coding_transcript_exon_variant	8/8
ZNF20	NM_001203250.2	c.1058G>A	p.Arg353Lys	missense_variant	4/4		NP_001190179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF20	ENST00000334213.10	c.1067G>A	p.Arg356Lys	missense_variant	4/4	1	NM_021143.4	ENSP00000335437	P1
	ENST00000601686.1	n.165-2656C>T		intron_variant, non_coding_transcript_variant		4
ZNF20	ENST00000600335.5	c.191+2381G>A		intron_variant		4		ENSP00000470025
ZNF20	ENST00000480770.5	n.221+2381G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.1067G>A (p.R356K) alteration is located in exon 4 (coding exon 4) of the ZNF20 gene. This alteration results from a G to A substitution at nucleotide position 1067, causing the arginine (R) at amino acid position 356 to be replaced by a lysine (K). 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	0.30
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.17
DANN	Benign	0.68
DEOGEN2	Benign	0.028	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.000020	N
LIST_S2	Benign	0.050	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.045	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.027
Sift	Benign	0.81	T
Sift4G	Benign	0.99	T
Polyphen		0.45	B
Vest4		0.032
MutPred		0.42		Gain of ubiquitination at R356 (P = 0.0082);
MVP		0.24
MPC		0.18
ClinPred		0.17	T
GERP RS		-1.9
Varity_R		0.036
gMVP		0.027

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: rs1976651096; hg19: chr19-12243934;