rs151023708

Variant names:

• chr19-21423174-A-G
• rs151023708
• NM_001076678.3:c.515A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001076678.3(ZNF493):​c.515A>G​(p.His172Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,613,790 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: ZNF493 NM_001076678.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.238
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020732164).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF493	NM_001076678.3	c.515A>G	p.His172Arg	missense_variant	Exon 4 of 4	ENST00000392288.7	NP_001070146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF493	ENST00000392288.7	c.515A>G	p.His172Arg	missense_variant	Exon 4 of 4	1	NM_001076678.3	ENSP00000376110.2
ENSG00000269237	ENST00000600810.1	n.196+17318A>G		intron_variant	Intron 2 of 4	3		ENSP00000473166.1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152262 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000372 AC: 93 AN: 250044 AF XY: 0.000362

Gnomad AFR exome AF: 0.000695

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000345

Gnomad OTH exome AF: 0.000988

GnomAD4 exome AF: 0.000231 AC: 337 AN: 1461410 Hom.: 3 Cov.: 32 AF XY: 0.000238 AC XY: 173 AN XY: 727000

African (AFR) AF: 0.000747 AC: 25 AN: 33448

American (AMR) AF: 0.000671 AC: 30 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00729 AC: 42 AN: 5758

European-Non Finnish (NFE) AF: 0.000138 AC: 153 AN: 1111798

Other (OTH) AF: 0.000762 AC: 46 AN: 60366

GnomAD4 genome AF: 0.000459 AC: 70 AN: 152380 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74516

African (AFR) AF: 0.000529 AC: 22 AN: 41606

American (AMR) AF: 0.00105 AC: 16 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000362 Hom.: 0

Bravo AF: 0.000499

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000363 AC: 44

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.515A>G (p.H172R) alteration is located in exon 4 (coding exon 4) of the ZNF493 gene. This alteration results from a A to G substitution at nucleotide position 515, causing the histidine (H) at amino acid position 172 to be replaced by an arginine (R). 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	0.070
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.6
DANN	Benign	0.93
DEOGEN2	Benign	0.25	.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.25	T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.021	T;T
MetaSVM	Uncertain	0.064	D
MutationAssessor	Pathogenic	3.9	.;H
PhyloP100		-0.24
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		0.0050	B;P
Vest4		0.087
MVP		0.83
MPC		0.012
ClinPred		0.091	T
GERP RS		1.1
Varity_R		0.15
gMVP		0.0026
Mutation Taster		=96/4	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: rs151023708; hg19: chr19-21605976;