Variant chr6-42978876-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_Moderate

The NM_000287.4(PEX6):c.275T>G(p.Val92Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,338,102 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. V92V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.34

Variant links:

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000287.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-42978876-A-C is Pathogenic according to our data. Variant chr6-42978876-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 224319.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX6	NM_000287.4 linkuse as main transcript	c.275T>G	p.Val92Gly	missense_variant	1/17	ENST00000304611.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX6	ENST00000304611.13 linkuse as main transcript	c.275T>G	p.Val92Gly	missense_variant	1/17	1	NM_000287.4	P1	Q13608-1
PEX6	ENST00000244546.4 linkuse as main transcript	c.275T>G	p.Val92Gly	missense_variant	1/15	1			Q13608-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.47e-7

AC:

AN:

1338102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

660254

show subpopulations

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:

9.42e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Heimler syndrome 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Leeds Amelogenesis Imperfecta Research Group, University of Leeds

Oct 01, 2015

Newly identified -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.58

T;T

M_CAP

Pathogenic

0.94

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Uncertain

0.72

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;T

Sift4G

Benign

0.67

T;D

Polyphen

1.0

D;.

Vest4

0.37

MutPred

0.38

Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);

MVP

0.99

MPC

4.0

ClinPred

0.98

GERP RS

4.9

Varity_R

0.73

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over