16-4752476-C-T

Variant names:

• chr16-4752476-C-T
• rs552222304
• NM_021646.4:c.1343G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021646.4(ZNF500):​c.1343G>A​(p.Arg448Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,545,228 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ZNF500 NM_021646.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.808
• Publications: 1 publications found

Genes affected

ZNF500 (HGNC:23716): (zinc finger protein 500) Predicted to enable DNA-binding transcription factor 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. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000266994 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05638653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF500	NM_021646.4	c.1343G>A	p.Arg448Gln	missense_variant	Exon 6 of 6	ENST00000219478.11	NP_067678.1
ZNF500	XM_005255243.5	c.992G>A	p.Arg331Gln	missense_variant	Exon 5 of 5		XP_005255300.1
ZNF500	NM_001303450.2	c.1297+46G>A		intron_variant	Intron 6 of 6		NP_001290379.1
ZNF500	XM_011522453.3	c.1297+46G>A		intron_variant	Intron 6 of 6		XP_011520755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF500	ENST00000219478.11	c.1343G>A	p.Arg448Gln	missense_variant	Exon 6 of 6	2	NM_021646.4	ENSP00000219478.5

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 151992 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000113 AC: 17 AN: 149898 AF XY: 0.000111

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.0000796

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000870

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 188 AN: 1393118 Hom.: 0 Cov.: 32 AF XY: 0.000132 AC XY: 91 AN XY: 688322

African (AFR) AF: 0.0000629 AC: 2 AN: 31774

American (AMR) AF: 0.0000552 AC: 2 AN: 36204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25266

East Asian (EAS) AF: 0.000472 AC: 17 AN: 36028

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79842

European-Finnish (FIN) AF: 0.000184 AC: 7 AN: 38024

Middle Eastern (MID) AF: 0.000357 AC: 2 AN: 5608

European-Non Finnish (NFE) AF: 0.000138 AC: 149 AN: 1082258

Other (OTH) AF: 0.000138 AC: 8 AN: 58114

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152110 Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9 AN XY: 74374

African (AFR) AF: 0.0000723 AC: 3 AN: 41492

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67968

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000623 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1343G>A (p.R448Q) alteration is located in exon 6 (coding exon 5) of the ZNF500 gene. This alteration results from a G to A substitution at nucleotide position 1343, causing the arginine (R) at amino acid position 448 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
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.36	N
PhyloP100		-0.81
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.088
Sift	Benign	0.045	D
Sift4G	Benign	0.33	T
Polyphen		0.93	P
Vest4		0.053
MVP		0.20
MPC		0.29
ClinPred		0.062	T
GERP RS		2.1
PromoterAI		0.014	Neutral
Varity_R		0.14
gMVP		0.11
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: rs552222304; hg19: chr16-4802477;