NM_000287.4:c.235G>C

Variant names:

• chr6-42978916-C-G
• rs61752141
• NM_000287.4:c.235G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000287.4(PEX6):​c.235G>C​(p.Ala79Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,486,432 control chromosomes in the GnomAD database, including 695 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A79T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (50 hom., cov: 33)
  • Exomes 𝑓: 0.029 (645 hom.)
• Consequence: PEX6 NM_000287.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.535
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027239919).
• BP6: Variant 6-42978916-C-G is Benign according to our data. Variant chr6-42978916-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0214 (3254/152214) while in subpopulation NFE AF = 0.0325 (2210/67982). AF 95% confidence interval is 0.0314. There are 50 homozygotes in GnomAd4. There are 1498 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 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.235G>C	p.Ala79Pro	missense	Exon 1 of 17	NP_000278.3
	PEX6	NM_001316313.2		c.235G>C	p.Ala79Pro	missense	Exon 1 of 17	NP_001303242.1	Q13608-3
	PEX6	NR_133009.2		n.266G>C		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.235G>C	p.Ala79Pro	missense	Exon 1 of 17	ENSP00000303511.8	Q13608-1
	PEX6	ENST00000244546.4	TSL:1	c.235G>C	p.Ala79Pro	missense	Exon 1 of 15	ENSP00000244546.4	Q13608-2
	PEX6	ENST00000858656.1		c.235G>C	p.Ala79Pro	missense	Exon 1 of 17	ENSP00000528715.1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3256 AN: 152106 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00541

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0752

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0246 AC: 2155 AN: 87674 AF XY: 0.0250

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00948

Gnomad ASJ exome AF: 0.0793

Gnomad EAS exome AF: 0.000203

Gnomad FIN exome AF: 0.0242

Gnomad NFE exome AF: 0.0315

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0291 AC: 38786 AN: 1334218 Hom.: 645 Cov.: 35 AF XY: 0.0288 AC XY: 18937 AN XY: 657942

African (AFR) AF: 0.00409 AC: 110 AN: 26910

American (AMR) AF: 0.0109 AC: 310 AN: 28412

Ashkenazi Jewish (ASJ) AF: 0.0812 AC: 1897 AN: 23368

East Asian (EAS) AF: 0.0000987 AC: 3 AN: 30408

South Asian (SAS) AF: 0.0132 AC: 973 AN: 73806

European-Finnish (FIN) AF: 0.0238 AC: 794 AN: 33338

Middle Eastern (MID) AF: 0.0125 AC: 49 AN: 3924

European-Non Finnish (NFE) AF: 0.0312 AC: 33051 AN: 1058704

Other (OTH) AF: 0.0289 AC: 1599 AN: 55348

GnomAD4 genome AF: 0.0214 AC: 3254 AN: 152214 Hom.: 50 Cov.: 33 AF XY: 0.0201 AC XY: 1498 AN XY: 74426

African (AFR) AF: 0.00539 AC: 224 AN: 41554

American (AMR) AF: 0.0137 AC: 209 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 261 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4832

European-Finnish (FIN) AF: 0.0218 AC: 231 AN: 10590

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0325 AC: 2210 AN: 67982

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0183 Hom.: 14

Bravo AF: 0.0205

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0371 AC: 143

ExAC AF: 0.0159 AC: 282

Asia WGS AF: 0.00494 AC: 18 AN: 3452

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Peroxisome biogenesis disorder (1)
-	-	1	Peroxisome biogenesis disorder 4A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.54
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.32	T
Polyphen		0.0040	B
Vest4		0.24
MPC		2.9
ClinPred		0.030	T
GERP RS		3.0
PromoterAI		-0.018	Neutral
Varity_R		0.24
gMVP		0.77
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61752141; hg19: chr6-42946654;