rs112822975

Variant names:

• chr7-92511010-C-G
• rs112822975
• NM_000466.3:c.1521G>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_000466.3(PEX1):​c.1521G>C​(p.Trp507Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,582,928 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (12 hom.)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0520
• Publications: 1 publications found

Genes affected

PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

PEX1 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 1A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, Myriad Women’s Health
• Heimler syndrome 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• peroxisome biogenesis disorder 1B

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000244055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056954324).
• BP6: Variant 7-92511010-C-G is Benign according to our data. Variant chr7-92511010-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00735 (1116/151856) while in subpopulation AFR AF = 0.0256 (1061/41404). AF 95% confidence interval is 0.0243. There are 16 homozygotes in GnomAd4. There are 527 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000466.3. 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
	PEX1	NM_000466.3	MANE Select	c.1521G>C	p.Trp507Cys	missense	Exon 8 of 24	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.1521G>C	p.Trp507Cys	missense	Exon 8 of 23	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.897G>C	p.Trp299Cys	missense	Exon 8 of 24	NP_001269607.1	B4DER6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	ENST00000248633.9	TSL:1 MANE Select	c.1521G>C	p.Trp507Cys	missense	Exon 8 of 24	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.1521G>C	p.Trp507Cys	missense	Exon 8 of 23	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.1521G>C	p.Trp507Cys	missense	Exon 8 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1110 AN: 151738 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

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: 0.0000294

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00171 AC: 427 AN: 249026 AF XY: 0.00124

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000695 AC: 995 AN: 1431072 Hom.: 12 Cov.: 26 AF XY: 0.000565 AC XY: 403 AN XY: 713792

African (AFR) AF: 0.0254 AC: 834 AN: 32834

American (AMR) AF: 0.00114 AC: 51 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00000829 AC: 9 AN: 1085064

Other (OTH) AF: 0.00169 AC: 100 AN: 59284

GnomAD4 genome AF: 0.00735 AC: 1116 AN: 151856 Hom.: 16 Cov.: 33 AF XY: 0.00710 AC XY: 527 AN XY: 74176

African (AFR) AF: 0.0256 AC: 1061 AN: 41404

American (AMR) AF: 0.00249 AC: 38 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67950

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00114 Hom.: 1

Bravo AF: 0.00835

ESP6500AA AF: 0.0215 AC: 91

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00208 AC: 252

Asia WGS AF: 0.00174 AC: 6 AN: 3470

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)
-	-	2	Zellweger spectrum disorders (2)
-	-	1	Peroxisome biogenesis disorder 1A (Zellweger) (1)
-	-	1	Peroxisome biogenesis disorder 1B;C4551980:Heimler syndrome 1;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0057	T
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.052
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.28
Sift	Benign	0.12	T
Sift4G	Benign	0.19	T
Polyphen		0.85	P
Vest4		0.42
MutPred		0.41		Gain of disorder (P = 0.0441)
MVP		0.89
MPC		0.25
ClinPred		0.0089	T
GERP RS		3.6
Varity_R		0.11
gMVP		0.58
Mutation Taster		=297/3	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: rs112822975; hg19: chr7-92140324; COSMIC: COSV50423711; COSMIC: COSV50423711;