rs886037780

chr6-42978876-A-Cchr6-42978876-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.34

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 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	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	c.275T>G	p.Val92Gly	missense_variant	1/17	1	NM_000287.4	P1
PEX6	ENST00000244546.4	c.275T>G	p.Val92Gly	missense_variant	1/15	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1338102 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 660254

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.052	T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.58	T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
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	D
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

Other links and lift over

dbSNP: rs886037780; hg19: chr6-42946614;