19-21405819-G-C

Variant names:

• chr19-21405819-G-C
• rs368590827
• NM_001076678.3:c.216G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001076678.3(ZNF493):​c.216G>C​(p.Trp72Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,547,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000061 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: ZNF493 NM_001076678.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.52
• Publications: 0 publications found

Genes affected

ZNF493 (HGNC:23708): (zinc finger protein 493) 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]

ENSG00000269237 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19481432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF493	NM_001076678.3	c.216G>C	p.Trp72Cys	missense_variant	Exon 3 of 4	ENST00000392288.7	NP_001070146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF493	ENST00000392288.7	c.216G>C	p.Trp72Cys	missense_variant	Exon 3 of 4	1	NM_001076678.3	ENSP00000376110.2
ENSG00000269237	ENST00000600810.1	n.159G>C		non_coding_transcript_exon_variant	Exon 2 of 5	3		ENSP00000473166.1

Frequencies

GnomAD3 genomes AF: 0.0000612 AC: 9 AN: 147130 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000222

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000718 AC: 18 AN: 250744 AF XY: 0.0000885

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: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000942 AC: 132 AN: 1400654 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 73 AN XY: 695740

African (AFR) AF: 0.00 AC: 0 AN: 31600

American (AMR) AF: 0.00 AC: 0 AN: 42650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23756

East Asian (EAS) AF: 0.00 AC: 0 AN: 34992

South Asian (SAS) AF: 0.000187 AC: 16 AN: 85522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47152

Middle Eastern (MID) AF: 0.000558 AC: 3 AN: 5380

European-Non Finnish (NFE) AF: 0.000103 AC: 111 AN: 1073332

Other (OTH) AF: 0.0000355 AC: 2 AN: 56270

GnomAD4 genome AF: 0.0000612 AC: 9 AN: 147130 Hom.: 0 Cov.: 30 AF XY: 0.0000280 AC XY: 2 AN XY: 71418

African (AFR) AF: 0.00 AC: 0 AN: 39912

American (AMR) AF: 0.00 AC: 0 AN: 14410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 4774

South Asian (SAS) AF: 0.000222 AC: 1 AN: 4496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9674

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000119 AC: 8 AN: 67180

Other (OTH) AF: 0.00 AC: 0 AN: 2044

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.216G>C (p.W72C) alteration is located in exon 3 (coding exon 3) of the ZNF493 gene. This alteration results from a G to C substitution at nucleotide position 216, causing the tryptophan (W) at amino acid position 72 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
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Benign	0.94
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.5
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-7.7	.;D;.;D
REVEL	Benign	0.086
Sift	Benign	0.057	.;T;.;T
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.34
MutPred		0.43		.;Loss of catalytic residue at W72 (P = 0.0042);Loss of catalytic residue at W72 (P = 0.0042);.;
MVP		0.41
MPC		0.012
ClinPred		0.36	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.055
Mutation Taster		=99/1	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: rs368590827; hg19: chr19-21588621;