rs35503676

Variant names:

• chr6-42978338-C-A
• rs35503676
• NM_000287.4:c.813G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-42978338-C-A
• chr6-42978338-C-G
• chr6-42978338-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000287.4(PEX6):​c.813G>T​(p.Ala271Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000919 in 1,614,172 control chromosomes in the GnomAD database, including 9 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. A271A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (3 hom.)
• Consequence: PEX6 NM_000287.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.377
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 6-42978338-C-A is Benign according to our data. Variant chr6-42978338-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.377 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00536 (817/152302) while in subpopulation AFR AF = 0.0187 (779/41554). AF 95% confidence interval is 0.0177. There are 6 homozygotes in GnomAd4. There are 378 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.813G>T	p.Ala271Ala	synonymous	Exon 1 of 17	NP_000278.3
	PEX6	NM_001316313.2		c.618+195G>T		intron	N/A	NP_001303242.1	Q13608-3
	PEX6	NR_133009.2		n.844G>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.813G>T	p.Ala271Ala	synonymous	Exon 1 of 17	ENSP00000303511.8	Q13608-1
	PEX6	ENST00000244546.4	TSL:1	c.813G>T	p.Ala271Ala	synonymous	Exon 1 of 15	ENSP00000244546.4	Q13608-2
	PEX6	ENST00000858656.1		c.813G>T	p.Ala271Ala	synonymous	Exon 1 of 17	ENSP00000528715.1

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 817 AN: 152184 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00141 AC: 354 AN: 251460 AF XY: 0.000979

Gnomad AFR exome AF: 0.0195

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000456 AC: 667 AN: 1461870 Hom.: 3 Cov.: 31 AF XY: 0.000408 AC XY: 297 AN XY: 727238

African (AFR) AF: 0.0167 AC: 558 AN: 33480

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111988

Other (OTH) AF: 0.000944 AC: 57 AN: 60396

GnomAD4 genome AF: 0.00536 AC: 817 AN: 152302 Hom.: 6 Cov.: 31 AF XY: 0.00508 AC XY: 378 AN XY: 74462

African (AFR) AF: 0.0187 AC: 779 AN: 41554

American (AMR) AF: 0.00216 AC: 33 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00153 Hom.: 2

Bravo AF: 0.00569

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Peroxisome biogenesis disorder (1)
-	-	1	Peroxisome biogenesis disorder 4A (Zellweger) (1)
-	-	1	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	7.9
DANN	Benign	0.81
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs35503676; hg19: chr6-42946076; COSMIC: COSV105846679;