chr1-10474986-C-T

Position:

• chr1-10474986-C-T

Variant summary

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

The NM_004565.3(PEX14):​c.20C>T​(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,376 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: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PEX14 NM_004565.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

Genes affected

PEX14 (HGNC:8856): (peroxisomal biogenesis factor 14) This gene encodes an essential component of the peroxisomal import machinery. The protein is integrated into peroxisome membranes with its C-terminus exposed to the cytosol, and interacts with the cytosolic receptor for proteins containing a PTS1 peroxisomal targeting signal. The protein also functions as a transcriptional corepressor and interacts with a histone deacetylase. A mutation in this gene results in one form of Zellweger syndrome. [provided by RefSeq, Jul 2008]

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
PEX14	NM_004565.3	c.20C>T	p.Ala7Val	missense_variant	1/9	ENST00000356607.9	NP_004556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX14	ENST00000356607.9	c.20C>T	p.Ala7Val	missense_variant	1/9	1	NM_004565.3	ENSP00000349016	P1
PEX14	ENST00000491661.2	c.5C>T	p.Ala2Val	missense_variant	1/6	2		ENSP00000465473
PEX14	ENST00000472851.1	n.293+2406C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457376 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724552

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder, complementation group K Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PEX14-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 7 of the PEX14 protein (p.Ala7Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.017
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.85	D;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.68	N;.
REVEL	Benign	0.072
Sift	Uncertain	0.015	D;.
Sift4G	Uncertain	0.043	D;D
Polyphen		0.19	B;.
Vest4		0.41
MutPred		0.094		Loss of helix (P = 0.0558);.;
MVP		0.44
MPC		0.42
ClinPred		0.90	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs759852702; hg19: chr1-10535043;