8-144882348-C-T

Variant names:

• chr8-144882348-C-T
• rs143751966
• NM_001109689.4:c.835G>A

Variant summary

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

The NM_001109689.4(ZNF250):​c.835G>A​(p.Glu279Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: ZNF250 NM_001109689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.05
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019613594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF250	NM_001109689.4	c.835G>A	p.Glu279Lys	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.835G>A	p.Glu279Lys	missense_variant	Exon 6 of 6	1	NM_001109689.4	ENSP00000393442.2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000439 AC: 11 AN: 250528 AF XY: 0.0000517

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000541 AC: 79 AN: 1461552 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727060

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

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

European-Non Finnish (NFE) AF: 0.0000558 AC: 62 AN: 1111816

Other (OTH) AF: 0.0000497 AC: 3 AN: 60370

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74458

African (AFR) AF: 0.000626 AC: 26 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000801 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.850G>A (p.E284K) alteration is located in exon 6 (coding exon 5) of the ZNF250 gene. This alteration results from a G to A substitution at nucleotide position 850, causing the glutamic acid (E) at amino acid position 284 to be replaced by a lysine (K). 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	0.22
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.047	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.020	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.45	N;.
PhyloP100		-1.0
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.17
Sift	Benign	0.34	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.96	D;.
Vest4		0.10
MVP		0.23
MPC		1.2
ClinPred		0.18	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.11
Mutation Taster		=100/0	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: rs143751966; hg19: chr8-146107733; COSMIC: COSV105117886; COSMIC: COSV105117886;