chr10-75399242-G-A

Position:

• chr10-75399242-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000372524.5(ZNF503):​c.1448C>T​(p.Thr483Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,439,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZNF503 ENST00000372524.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36

Genes affected

ZNF503 (HGNC:23589): (zinc finger protein 503) Predicted to enable metal ion binding activity. Involved in G1 to G0 transition involved in cell differentiation; negative regulation of cell population proliferation; and negative regulation of gene expression. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000270087 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF503	NM_032772.6	c.1448C>T	p.Thr483Met	missense_variant	2/2	ENST00000372524.5	NP_116161.2
ZNF503	NR_120651.2	n.812+1863C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF503	ENST00000372524.5	c.1448C>T	p.Thr483Met	missense_variant	2/2	1	NM_032772.6	ENSP00000361602.4
ENSG00000270087	ENST00000418818.6	n.142+1863C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439318 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 713518

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Feb 13, 2024

The c.1448C>T (p.T483M) alteration is located in exon 2 (coding exon 2) of the ZNF503 gene. This alteration results from a C to T substitution at nucleotide position 1448, causing the threonine (T) at amino acid position 483 to be replaced by a methionine (M). 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	0.32
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0079	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	0.91	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.19
Sift	Benign	0.068	T
Sift4G	Benign	0.067	T
Polyphen		0.99	D
Vest4		0.62
MutPred		0.28		Loss of glycosylation at T483 (P = 0.0036);
MVP		0.24
MPC		0.68
ClinPred		0.71	D
GERP RS		4.5
Varity_R		0.070
gMVP		0.62

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: rs1206280988; hg19: chr10-77159000;