rs9462858

Variant names:

• chr6-42978752-C-A
• rs9462858
• NM_000287.4:c.399G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-42978752-C-A
• chr6-42978752-C-G
• chr6-42978752-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000287.4(PEX6):​c.399G>T​(p.Val133Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,535,058 control chromosomes in the GnomAD database, including 145,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V133V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.40 (12678 hom., cov: 32)
  • Exomes 𝑓: 0.43 (133220 hom.)
• Consequence: PEX6 NM_000287.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.405
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 6-42978752-C-A is Benign according to our data. Variant chr6-42978752-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.405 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000287.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX6	NM_000287.4	MANE Select	c.399G>T	p.Val133Val	synonymous	Exon 1 of 17	NP_000278.3
	PEX6	NM_001316313.2		c.399G>T	p.Val133Val	synonymous	Exon 1 of 17	NP_001303242.1	Q13608-3
	PEX6	NR_133009.2		n.430G>T		non_coding_transcript_exon	Exon 1 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX6	ENST00000304611.13	TSL:1 MANE Select	c.399G>T	p.Val133Val	synonymous	Exon 1 of 17	ENSP00000303511.8	Q13608-1
	PEX6	ENST00000244546.4	TSL:1	c.399G>T	p.Val133Val	synonymous	Exon 1 of 15	ENSP00000244546.4	Q13608-2
	PEX6	ENST00000858656.1		c.399G>T	p.Val133Val	synonymous	Exon 1 of 17	ENSP00000528715.1

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61088 AN: 151720 Hom.: 12674 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.585

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.406

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.416

GnomAD2 exomes AF: 0.377 AC: 49572 AN: 131414 AF XY: 0.388

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.266

Gnomad ASJ exome AF: 0.418

Gnomad EAS exome AF: 0.106

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.454

Gnomad OTH exome AF: 0.415

GnomAD4 exome AF: 0.434 AC: 600230 AN: 1383220 Hom.: 133220 Cov.: 68 AF XY: 0.435 AC XY: 296994 AN XY: 682622

African (AFR) AF: 0.378 AC: 11950 AN: 31590

American (AMR) AF: 0.283 AC: 10094 AN: 35720

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 10390 AN: 25116

East Asian (EAS) AF: 0.127 AC: 4535 AN: 35796

South Asian (SAS) AF: 0.434 AC: 34435 AN: 79276

European-Finnish (FIN) AF: 0.389 AC: 13277 AN: 34158

Middle Eastern (MID) AF: 0.471 AC: 2369 AN: 5030

European-Non Finnish (NFE) AF: 0.453 AC: 489116 AN: 1078746

Other (OTH) AF: 0.416 AC: 24064 AN: 57788

GnomAD4 genome AF: 0.403 AC: 61125 AN: 151838 Hom.: 12678 Cov.: 32 AF XY: 0.398 AC XY: 29568 AN XY: 74204

African (AFR) AF: 0.374 AC: 15473 AN: 41424

American (AMR) AF: 0.339 AC: 5182 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1415 AN: 3470

East Asian (EAS) AF: 0.103 AC: 530 AN: 5140

South Asian (SAS) AF: 0.405 AC: 1947 AN: 4810

European-Finnish (FIN) AF: 0.406 AC: 4285 AN: 10560

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.454 AC: 30767 AN: 67842

Other (OTH) AF: 0.413 AC: 873 AN: 2112

Alfa AF: 0.424 Hom.: 2492

Bravo AF: 0.394

Asia WGS AF: 0.260 AC: 905 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	2	Peroxisome biogenesis disorder 4A (Zellweger) (2)
-	-	1	Heimler syndrome 2 (1)
-	-	1	Peroxisome biogenesis disorder (1)
-	-	1	Peroxisome biogenesis disorder 4B (1)
-	-	1	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		0.41
PromoterAI		0.14	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9462858; hg19: chr6-42946490; COSMIC: COSV55102374;