rs766646721

Variant names:

• chr19-21405133-C-A
• rs766646721
• NM_001076678.3:c.35C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-21405133-C-A
• chr19-21405133-C-T

Variant summary

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

The NM_001076678.3(ZNF493):​c.35C>A​(p.Pro12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,582 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 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ZNF493 NM_001076678.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0550
• Publications: 1 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=0.11286831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF493	NM_001076678.3	c.35C>A	p.Pro12Gln	missense_variant	Exon 2 of 4	ENST00000392288.7	NP_001070146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF493	ENST00000392288.7	c.35C>A	p.Pro12Gln	missense_variant	Exon 2 of 4	1	NM_001076678.3	ENSP00000376110.2
ENSG00000269237	ENST00000600810.1	n.-26C>A		upstream_gene_variant		3		ENSP00000473166.1

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151678 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000527

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250718 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460904 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 726788

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.000112 AC: 5 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111560

Other (OTH) AF: 0.0000331 AC: 2 AN: 60342

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151678 Hom.: 0 Cov.: 32 AF XY: 0.0000675 AC XY: 5 AN XY: 74052

African (AFR) AF: 0.0000243 AC: 1 AN: 41236

American (AMR) AF: 0.000527 AC: 8 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000208

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35C>A (p.P12Q) alteration is located in exon 2 (coding exon 2) of the ZNF493 gene. This alteration results from a C to A substitution at nucleotide position 35, causing the proline (P) at amino acid position 12 to be replaced by a glutamine (Q). 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	-0.40	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.7
DANN	Benign	0.93
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.033	T;T;T;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.055
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.7	.;D;.;D
REVEL	Benign	0.061
Sift	Benign	0.26	.;T;.;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		1.0	.;D;.;.
Vest4		0.25
MutPred		0.36		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.20
MPC		0.063
ClinPred		0.28	T
GERP RS		-2.0
gMVP		0.071
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs766646721; hg19: chr19-21587935;