6-136822705-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_000288.4(PEX7):c.40A>T(p.Thr14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,365,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T14P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

PEX7
NM_000288.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.789

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-136822705-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.25396037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX7	NM_000288.4 link	c.40A>T	p.Thr14Ser	missense_variant	Exon 1 of 10	ENST00000318471.5	NP_000279.1	O00628-1Q6FGN1
PEX7	XM_006715502.3 link	c.40A>T	p.Thr14Ser	missense_variant	Exon 1 of 7		XP_006715565.1
PEX7	XM_047418874.1 link	c.40A>T	p.Thr14Ser	missense_variant	Exon 1 of 6		XP_047274830.1
PEX7	NM_001410945.1 link	c.-659A>T		upstream_gene_variant			NP_001397874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5 link	c.40A>T	p.Thr14Ser	missense_variant	Exon 1 of 10	1	NM_000288.4	ENSP00000315680.3		O00628-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.32e-7

AC:

AN:

1365516

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

674002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28836

American (AMR)

AF:

0.00

AC:

AN:

34364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24456

East Asian (EAS)

AF:

0.00

AC:

AN:

33696

South Asian (SAS)

AF:

0.00

AC:

AN:

77858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33746

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

9.33e-7

AC:

AN:

1071604

Other (OTH)

AF:

0.00

AC:

AN:

56824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.24

.;T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.41

T;T;T

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.8

L;.;L

PhyloP100

0.79

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.23

Sift

Benign

0.042

D;D;T

Sift4G

Benign

0.11

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.094

MutPred

0.52

Gain of disorder (P = 0.0292);Gain of disorder (P = 0.0292);Gain of disorder (P = 0.0292);

MVP

0.97

MPC

0.11

ClinPred

0.16

GERP RS

2.1

PromoterAI

-0.081

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.088

gMVP

0.36

Mutation Taster

=77/23

polymorphism

(source)

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

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