NM_000287.4:c.1130+1068T>C

Variant names:

• chr6-42972935-A-G
• rs2395943
• NM_000287.4:c.1130+1068T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000287.4(PEX6):​c.1130+1068T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.663 in 152,096 control chromosomes in the GnomAD database, including 35,517 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (35517 hom., cov: 31)
• Consequence: PEX6 NM_000287.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• Publications: 66 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.1130+1068T>C		intron_variant	Intron 3 of 16	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000304611.13	c.1130+1068T>C		intron_variant	Intron 3 of 16	1	NM_000287.4	ENSP00000303511.8
PEX6	ENST00000244546.4	c.1130+1068T>C		intron_variant	Intron 3 of 14	1		ENSP00000244546.4

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100751 AN: 151978 Hom.: 35461 Cov.: 31

Gnomad AFR AF: 0.917

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.649

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.663 AC: 100870 AN: 152096 Hom.: 35517 Cov.: 31 AF XY: 0.656 AC XY: 48784 AN XY: 74336

African (AFR) AF: 0.917 AC: 38075 AN: 41520

American (AMR) AF: 0.587 AC: 8967 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1771 AN: 3466

East Asian (EAS) AF: 0.335 AC: 1732 AN: 5164

South Asian (SAS) AF: 0.642 AC: 3096 AN: 4822

European-Finnish (FIN) AF: 0.523 AC: 5520 AN: 10562

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39534 AN: 67972

Other (OTH) AF: 0.651 AC: 1377 AN: 2114

Alfa AF: 0.602 Hom.: 125512

Bravo AF: 0.678

Asia WGS AF: 0.545 AC: 1898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	9.9
DANN	Benign	0.54
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs2395943; hg19: chr6-42940673;