rs34551839

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000287.4(PEX6):​c.2770G>T​(p.Ala924Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000989 in 1,614,140 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 6 hom., cov: 32)
Exomes 𝑓: 0.00050 ( 3 hom. )

Consequence

PEX6
NM_000287.4 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.425
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.007917464).
BP6
Variant 6-42964826-C-A is Benign according to our data. Variant chr6-42964826-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 235682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42964826-C-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00569 (866/152266) while in subpopulation AFR AF= 0.0196 (813/41536). AF 95% confidence interval is 0.0185. There are 6 homozygotes in gnomad4. There are 406 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PEX6NM_000287.4 linkuse as main transcriptc.2770G>T p.Ala924Ser missense_variant 16/17 ENST00000304611.13 NP_000278.3 Q13608-1A0A024RD09

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PEX6ENST00000304611.13 linkuse as main transcriptc.2770G>T p.Ala924Ser missense_variant 16/171 NM_000287.4 ENSP00000303511.8 Q13608-1
PEX6ENST00000244546 linkuse as main transcriptc.*306G>T 3_prime_UTR_variant 14/151 ENSP00000244546.4 Q13608-2

Frequencies

GnomAD3 genomes
AF:
0.00569
AC:
866
AN:
152148
Hom.:
6
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0196
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00308
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:
0.00287
GnomAD3 exomes
AF:
0.00151
AC:
379
AN:
251220
Hom.:
3
AF XY:
0.00103
AC XY:
140
AN XY:
135776
show subpopulations
Gnomad AFR exome
AF:
0.0204
Gnomad AMR exome
AF:
0.00127
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000499
AC:
730
AN:
1461874
Hom.:
3
Cov.:
34
AF XY:
0.000440
AC XY:
320
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.0178
Gnomad4 AMR exome
AF:
0.00116
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.00104
GnomAD4 genome
AF:
0.00569
AC:
866
AN:
152266
Hom.:
6
Cov.:
32
AF XY:
0.00545
AC XY:
406
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.0196
Gnomad4 AMR
AF:
0.00307
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00287
Hom.:
4
Bravo
AF:
0.00601
ESP6500AA
AF:
0.0184
AC:
81
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00188
AC:
228
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsOct 28, 2015- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 12, 2020- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 26, 2020Variant summary: PEX6 c.2770G>T (p.Ala924Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251220 control chromosomes, predominantly at a frequency of 0.02 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX6 causing Zellweger Syndrome phenotype (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.2770G>T in individuals affected with Zellweger Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2)/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Peroxisome biogenesis disorder 4A (Zellweger) Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Zellweger spectrum disorders Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Dec 06, 2019- -
Peroxisome biogenesis disorder Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
4.4
DANN
Benign
0.85
DEOGEN2
Benign
0.030
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.084
N
LIST_S2
Benign
0.82
T
MetaRNN
Benign
0.0079
T
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
0.47
N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
0.58
N
REVEL
Benign
0.15
Sift
Benign
0.53
T
Sift4G
Benign
0.72
T
Polyphen
0.0
B
Vest4
0.23
MVP
0.73
MPC
0.13
ClinPred
0.0019
T
GERP RS
-2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.023
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34551839; hg19: chr6-42932564; COSMIC: COSV105846678; COSMIC: COSV105846678; API