rs61753233

Positions:

• chr6-136822705-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_000288.4(PEX7):​c.40A>C​(p.Thr14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,365,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PEX7 NM_000288.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 0.789

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 6-136822705-A-C is Pathogenic according to our data. Variant chr6-136822705-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 7790.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-136822705-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX7	NM_000288.4	c.40A>C	p.Thr14Pro	missense_variant	1/10	ENST00000318471.5	NP_000279.1
PEX7	XM_006715502.3	c.40A>C	p.Thr14Pro	missense_variant	1/7		XP_006715565.1
PEX7	XM_047418874.1	c.40A>C	p.Thr14Pro	missense_variant	1/6		XP_047274830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5	c.40A>C	p.Thr14Pro	missense_variant	1/10	1	NM_000288.4	ENSP00000315680.3
PEX7	ENST00000367756.8	c.40A>C	p.Thr14Pro	missense_variant	1/4	3		ENSP00000356730.4
PEX7	ENST00000541292.6	n.40A>C		non_coding_transcript_exon_variant	1/11	5		ENSP00000441004.1
PEX7	ENST00000678593.1	n.40A>C		non_coding_transcript_exon_variant	1/8			ENSP00000503841.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000132 AC: 18 AN: 1365516 Hom.: 0 Cov.: 33 AF XY: 0.0000119 AC XY: 8 AN XY: 674002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000168

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 9B Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -

Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2024

- -

Rhizomelic chondrodysplasia punctata type 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	.;T;D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.49	T;T;T
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.044	D;T;D
Polyphen		0.20	.;.;B
Vest4		0.68
MutPred		0.81		Gain of disorder (P = 0.0267);Gain of disorder (P = 0.0267);Gain of disorder (P = 0.0267);
MVP		0.99
MPC		0.39
ClinPred		0.92	D
GERP RS		2.1
Varity_R		0.43
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs61753233; hg19: chr6-137143843;