17-15716062-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_001288644.2(ZNF286A):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ZNF286A
NM_001288644.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00400

Variant links:

Genes affected

ZNF286A (HGNC:13501): (zinc finger protein 286A) 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. Predicted to be integral component of membrane. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF286A links:

ZNF286A-TBC1D26 (HGNC:55384): (ZNF286A-TBC1D26 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring ZNF286A and TBC1D26 genes. This transcript is thought to be non-coding because it would be subject to nonsense-mediated mRNA decay (NMD). [provided by RefSeq, Nov 2020]

ZNF286A-TBC1D26 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 64 codons. Genomic position: 15716250. Lost 0.154 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF286A	NM_001130842.2 link	c.338T>C	p.Met113Thr	missense_variant	Exon 6 of 6	ENST00000583566.6	NP_001124314.1	Q9HBT8-1B2RCD9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF286A	ENST00000583566.6 link	c.338T>C	p.Met113Thr	missense_variant	Exon 6 of 6	1	NM_001130842.2	ENSP00000464063.1		Q9HBT8-1
ZNF286A-TBC1D26	ENST00000413242.6 link	n.338T>C		non_coding_transcript_exon_variant	Exon 6 of 17	2		ENSP00000458062.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461530

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111788

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000624

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.338T>C (p.M113T) alteration is located in exon 6 (coding exon 5) of the ZNF286A gene. This alteration results from a T to C substitution at nucleotide position 338, causing the methionine (M) at amino acid position 113 to be replaced by a threonine (T). 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

0.065

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.35

DEOGEN2

Benign

0.012

T;.;T;.;.;T

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.097

T;T;.;D;T;.

M_CAP

Benign

0.0030

MetaRNN

Benign

0.042

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

L;.;L;.;.;L

PhyloP100

0.0040

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.86

N;.;.;.;.;.

REVEL

Benign

0.083

Sift

Benign

0.15

T;.;.;.;.;.

Sift4G

Benign

0.37

T;T;T;D;T;T

Polyphen

0.0010

B;.;B;.;.;B

Vest4

0.052

MutPred

0.23

Gain of phosphorylation at M113 (P = 0.0168);.;Gain of phosphorylation at M113 (P = 0.0168);.;.;Gain of phosphorylation at M113 (P = 0.0168);

MVP

0.27

MPC

0.073

ClinPred

0.095

GERP RS

0.38

Varity_R

0.060

gMVP

0.12

Mutation Taster

=97/3

polymorphism

(source)

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

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17-15716062-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over