Genetic Variant NM_000466.3:c.2584-12_2584-10delTTT (chr7-92499847-CAAA-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000466.3(PEX1):c.2584-12_2584-10delTTT variant causes a intron change. The variant allele was found at a frequency of 0.000181 in 1,174,010 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PEX1
NM_000466.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.05

Publications

6 publications found

Variant links:

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: Myriad Women’s Health, Ambry Genetics
Heimler syndrome 1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3 link	c.2584-12_2584-10delTTT		intron_variant	Intron 15 of 23	ENST00000248633.9	NP_000457.1	O43933-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9 link	c.2584-12_2584-10delTTT		intron_variant	Intron 15 of 23	1	NM_000466.3	ENSP00000248633.4		O43933-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146154

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.000130

AC:

AN:

153898

AF XY:

0.000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000137

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000222

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000181

AC:

212

AN:

1174010

Hom.:

AF XY:

0.000176

AC XY:

104

AN XY:

589866

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000140

AC:

AN:

28602

American (AMR)

AF:

0.000129

AC:

AN:

38698

Ashkenazi Jewish (ASJ)

AF:

0.0000446

AC:

AN:

22408

East Asian (EAS)

AF:

0.0000282

AC:

AN:

35434

South Asian (SAS)

AF:

0.000222

AC:

AN:

72200

European-Finnish (FIN)

AF:

0.000178

AC:

AN:

44870

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4982

European-Non Finnish (NFE)

AF:

0.000194

AC:

170

AN:

877240

Other (OTH)

AF:

0.000141

AC:

AN:

49576

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.241

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

146154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71200

African (AFR)

AF:

0.00

AC:

AN:

39220

American (AMR)

AF:

0.00

AC:

AN:

14732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3382

East Asian (EAS)

AF:

0.00

AC:

AN:

4982

South Asian (SAS)

AF:

0.00

AC:

AN:

4666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66444

Other (OTH)

AF:

0.00

AC:

AN:

2006

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over