chr8-144881640-A-G

Variant names:

• chr8-144881640-A-G
• NM_001109689.4:c.1543T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001109689.4(ZNF250):​c.1543T>C​(p.Ser515Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,760 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: 6.8e-7 (0 hom.)
• Consequence: ZNF250 NM_001109689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.221
• Publications: 0 publications found

Genes affected

ZNF250 (HGNC:13044): (zinc finger protein 250) Enables identical protein binding activity and sequence-specific double-stranded 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF250	NM_001109689.4	c.1543T>C	p.Ser515Pro	missense_variant	Exon 6 of 6	ENST00000417550.7	NP_001103159.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF250	ENST00000417550.7	c.1543T>C	p.Ser515Pro	missense_variant	Exon 6 of 6	1	NM_001109689.4	ENSP00000393442.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111940

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1558T>C (p.S520P) alteration is located in exon 6 (coding exon 5) of the ZNF250 gene. This alteration results from a T to C substitution at nucleotide position 1558, causing the serine (S) at amino acid position 520 to be replaced by a proline (P). 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	0.96
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.27	T;T
M_CAP	Benign	0.0054	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		0.22
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		1.0	D;.
Vest4		0.45
MutPred		0.69		Loss of catalytic residue at S520 (P = 0.1115);.;
MVP		0.52
MPC		1.5
ClinPred		0.95	D
GERP RS		4.1
Varity_R		0.77
gMVP		0.40
Mutation Taster		=94/6	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

hg19: chr8-146107025;