rs35996821

Variant names:

• chr7-92503179-T-C
• rs35996821
• NM_000466.3:c.2088A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000466.3(PEX1):​c.2088A>G​(p.Ile696Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,613,270 control chromosomes in the GnomAD database, including 1,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. I696V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (56 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1011 hom.)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0440
• Publications: 17 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=0.003272444).
• BP6: Variant 7-92503179-T-C is Benign according to our data. Variant chr7-92503179-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

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.2088A>G	p.Ile696Met	missense	Exon 13 of 24	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.1917A>G	p.Ile639Met	missense	Exon 12 of 23	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.1464A>G	p.Ile488Met	missense	Exon 13 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.2088A>G	p.Ile696Met	missense	Exon 13 of 24	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.1917A>G	p.Ile639Met	missense	Exon 12 of 23	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.2088A>G	p.Ile696Met	missense	Exon 13 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes AF: 0.0254 AC: 3868 AN: 152178 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.00736

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0387

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0271 AC: 6802 AN: 251034 AF XY: 0.0283

Gnomad AFR exome AF: 0.00646

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.0425

Gnomad EAS exome AF: 0.00365

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0382

Gnomad OTH exome AF: 0.0327

GnomAD4 exome AF: 0.0348 AC: 50800 AN: 1460974 Hom.: 1011 Cov.: 31 AF XY: 0.0346 AC XY: 25173 AN XY: 726872

African (AFR) AF: 0.00666 AC: 223 AN: 33468

American (AMR) AF: 0.0161 AC: 719 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0402 AC: 1050 AN: 26118

East Asian (EAS) AF: 0.00315 AC: 125 AN: 39636

South Asian (SAS) AF: 0.0214 AC: 1846 AN: 86238

European-Finnish (FIN) AF: 0.0221 AC: 1181 AN: 53322

Middle Eastern (MID) AF: 0.0628 AC: 362 AN: 5760

European-Non Finnish (NFE) AF: 0.0389 AC: 43213 AN: 1111360

Other (OTH) AF: 0.0345 AC: 2081 AN: 60362

GnomAD4 genome AF: 0.0254 AC: 3865 AN: 152296 Hom.: 56 Cov.: 32 AF XY: 0.0247 AC XY: 1836 AN XY: 74464

African (AFR) AF: 0.00734 AC: 305 AN: 41578

American (AMR) AF: 0.0216 AC: 331 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 131 AN: 3468

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5182

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4826

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10612

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0386 AC: 2628 AN: 68010

Other (OTH) AF: 0.0303 AC: 64 AN: 2114

Alfa AF: 0.0339 Hom.: 220

Bravo AF: 0.0260

TwinsUK AF: 0.0340 AC: 126

ALSPAC AF: 0.0314 AC: 121

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0402 AC: 346

ExAC AF: 0.0267 AC: 3238

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0445

EpiControl AF: 0.0411

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Benign	0.61
DEOGEN2	Benign	0.29	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.66	N
PhyloP100		-0.044
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.19
Sift	Benign	0.18	T
Sift4G	Benign	0.29	T
Polyphen		0.0020	B
Vest4		0.044
MPC		0.17
ClinPred		0.0043	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.50
Mutation Taster		=88/12	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: rs35996821; hg19: chr7-92132493; COSMIC: COSV104373578;