dbSNP rs61753238: PEX7:p.Tyr40* (chr6-136822785-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000288.4(PEX7):c.120C>A(p.Tyr40*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000835 in 1,198,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y40Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

PEX7
NM_000288.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

Publications

6 publications found

Variant links:

Genes affected

PEX7 (HGNC:8860): (peroxisomal biogenesis factor 7) This gene encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Defects in this gene cause peroxisome biogenesis disorders (PBDs), which are characterized by multiple defects in peroxisome function. There are at least 14 complementation groups for PBDs, with more than one phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene have been associated with PBD complementation group 11 (PBD-CG11) disorders, rhizomelic chondrodysplasia punctata type 1 (RCDP1), and Refsum disease (RD). [provided by RefSeq, Oct 2008]

PEX7 Gene-Disease associations (from GenCC):

peroxisome biogenesis disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
peroxisome biogenesis disorder 9B
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
rhizomelic chondrodysplasia punctata type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
adult Refsum disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PEX7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX7	NM_000288.4 link	c.120C>A	p.Tyr40*	stop_gained	Exon 1 of 10	ENST00000318471.5	NP_000279.1	O00628-1Q6FGN1
PEX7	XM_006715502.3 link	c.120C>A	p.Tyr40*	stop_gained	Exon 1 of 7		XP_006715565.1
PEX7	XM_047418874.1 link	c.120C>A	p.Tyr40*	stop_gained	Exon 1 of 6		XP_047274830.1
PEX7	NM_001410945.1 link	c.-579C>A		upstream_gene_variant			NP_001397874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5 link	c.120C>A	p.Tyr40*	stop_gained	Exon 1 of 10	1	NM_000288.4	ENSP00000315680.3		O00628-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000416

AC:

AN:

24010

AF XY:

0.0000655

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.35e-7

AC:

AN:

1198062

Hom.:

Cov.:

AF XY:

0.00000171

AC XY:

AN XY:

583098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24024

American (AMR)

AF:

0.00

AC:

AN:

12096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17590

East Asian (EAS)

AF:

0.00

AC:

AN:

26454

South Asian (SAS)

AF:

0.00

AC:

AN:

48838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3414

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

987914

Other (OTH)

AF:

0.00

AC:

AN:

48802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.90

PhyloP100

1.5

Vest4

0.79

GERP RS

5.3

PromoterAI

-0.24

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=0/200

disease causing (fs/PTC)

(source)

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over