15-89683648-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003847.3(PEX11A):c.473A>T(p.Lys158Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX11A NM_003847.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.766

Genes affected

PEX11A (HGNC:8852): (peroxisomal biogenesis factor 11 alpha) This gene is a member of the PEX11 family, which is composed of membrane elongation factors involved in regulation of peroxisome maintenance and proliferation. This gene product interacts with peroxisomal membrane protein 19 and may respond to outside stimuli to increase peroxisome abundance. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2590184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX11A	NM_003847.3	c.473A>T	p.Lys158Ile	missense_variant	3/3	ENST00000300056.8
PEX11A	NM_001271572.2	c.380A>T	p.Lys127Ile	missense_variant	3/3
PEX11A	NM_001271573.2	c.38A>T	p.Lys13Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX11A	ENST00000300056.8	c.473A>T	p.Lys158Ile	missense_variant	3/3	1	NM_003847.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Sep 17, 2021

The c.473A>T (p.K158I) alteration is located in exon 3 (coding exon 3) of the PEX11A gene. This alteration results from a A to T substitution at nucleotide position 473, causing the lysine (K) at amino acid position 158 to be replaced by an isoleucine (I). 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	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.15
Sift	Benign	0.034	D;D
Sift4G	Uncertain	0.027	D;T
Polyphen		0.90	P;.
Vest4		0.26
MutPred		0.44		Loss of ubiquitination at K158 (P = 0.0155);.;
MVP		0.56
MPC		0.33
ClinPred		0.35	T
GERP RS		2.0
Varity_R		0.14
gMVP		0.40

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: rs1964631429; hg19: chr15-90226879;