chr17-15716062-T-C

Position:

• chr17-15716062-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00400

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-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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF286A	NM_001130842.2	c.338T>C	p.Met113Thr	missense_variant	6/6	ENST00000583566.6	NP_001124314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF286A	ENST00000583566.6	c.338T>C	p.Met113Thr	missense_variant	6/6	1	NM_001130842.2	ENSP00000464063.1
ZNF286A-TBC1D26	ENST00000413242.6	n.338T>C		non_coding_transcript_exon_variant	6/17	2		ENSP00000458062.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461530 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.00000378

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

Nov 30, 2022

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	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
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	N
LIST_S2	Benign	0.097	T;T;.;D;T;.
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.042	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.;L;.;.;L
PrimateAI	Benign	0.23	T
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	T
GERP RS		0.38
Varity_R		0.060
gMVP		0.12

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: rs1197492300; hg19: chr17-15619376;