chr6-42978876-A-C

Variant names:

• chr6-42978876-A-C
• rs886037780
• NM_000287.4:c.275T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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, 11 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 VariationId is 224319.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.275T>G	p.Val92Gly	missense_variant	Exon 1 of 17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.275T>G	p.Val92Gly	missense_variant	Exon 1 of 17	1	NM_000287.4	ENSP00000303511.8
PEX6	ENST00000244546.4	c.275T>G	p.Val92Gly	missense_variant	Exon 1 of 15	1		ENSP00000244546.4

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

African (AFR) AF: 0.00 AC: 0 AN: 26966

American (AMR) AF: 0.00 AC: 0 AN: 28636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23148

East Asian (EAS) AF: 0.00 AC: 0 AN: 31220

South Asian (SAS) AF: 0.00 AC: 0 AN: 74130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3898

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061302

Other (OTH) AF: 0.00 AC: 0 AN: 55586

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Heimler syndrome 2 Pathogenic:1

Oct 01, 2015

Leeds Amelogenesis Imperfecta Research Group, University of Leeds

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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
PhyloP100		3.3
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
PromoterAI		0.061	Neutral
Varity_R		0.73
gMVP		0.73
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886037780; hg19: chr6-42946614;