Genetic Variant NM_000466.3:c.2442C>T (chr7-92501648-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_000466.3(PEX1):c.2442C>T(p.Phe814Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,613,742 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 14 hom. )

Consequence

PEX1
NM_000466.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.62

Publications

5 publications found

Variant links:

COSMIC-nc: COSV104373605

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

PEX1 links:

ENSG00000244055 (HGNC:):

ENSG00000244055 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 7-92501648-G-A is Benign according to our data. Variant chr7-92501648-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93106.

BP7

Synonymous conserved (PhyloP=1.62 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00228 (347/152224) while in subpopulation NFE AF = 0.0034 (231/68012). AF 95% confidence interval is 0.00304. There are 2 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX1	NM_000466.3	MANE Select	c.2442C>T	p.Phe814Phe	synonymous	Exon 15 of 24	NP_000457.1	O43933-1
PEX1	NM_001282677.2		c.2271C>T	p.Phe757Phe	synonymous	Exon 14 of 23	NP_001269606.1	A0A0C4DG33
PEX1	NM_001282678.2		c.1818C>T	p.Phe606Phe	synonymous	Exon 15 of 24	NP_001269607.1	B4DER6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX1	ENST00000248633.9	TSL:1 MANE Select	c.2442C>T	p.Phe814Phe	synonymous	Exon 15 of 24	ENSP00000248633.4	O43933-1
PEX1	ENST00000428214.5	TSL:1	c.2271C>T	p.Phe757Phe	synonymous	Exon 14 of 23	ENSP00000394413.1	A0A0C4DG33
PEX1	ENST00000951788.1		c.2442C>T	p.Phe814Phe	synonymous	Exon 15 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

345

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00340

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00236

AC:

593

AN:

251264

AF XY:

0.00254

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00333

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00289

AC:

4219

AN:

1461518

Hom.:

Cov.:

AF XY:

0.00291

AC XY:

2117

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

33470

American (AMR)

AF:

0.00233

AC:

104

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00199

AC:

172

AN:

86248

European-Finnish (FIN)

AF:

0.000599

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0250

AC:

144

AN:

5766

European-Non Finnish (NFE)

AF:

0.00306

AC:

3403

AN:

1111706

Other (OTH)

AF:

0.00373

AC:

225

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

202

403

605

806

1008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00228

AC:

347

AN:

152224

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

167

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41546

American (AMR)

AF:

0.00301

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00166

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00340

AC:

231

AN:

68012

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00272

Hom.:

Bravo

AF:

0.00252

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00533

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Zellweger spectrum disorders (2)

Peroxisome biogenesis disorder 1A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

1.6

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over