chr6-136822781-A-C

Position:

• chr6-136822781-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The ENST00000318471.5(PEX7):​c.116A>C​(p.His39Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000829 in 1,206,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H39Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: PEX7 ENST00000318471.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.25

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-136822781-A-C is Pathogenic according to our data. Variant chr6-136822781-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 813362.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}. Variant chr6-136822781-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.116A>C	p.His39Pro	missense_variant	1/10	ENST00000318471.5	NP_000279.1
PEX7	XM_006715502.3	c.116A>C	p.His39Pro	missense_variant	1/7		XP_006715565.1
PEX7	XM_047418874.1	c.116A>C	p.His39Pro	missense_variant	1/6		XP_047274830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5	c.116A>C	p.His39Pro	missense_variant	1/10	1	NM_000288.4	ENSP00000315680	P1
PEX7	ENST00000367756.8	c.116A>C	p.His39Pro	missense_variant	1/4	3		ENSP00000356730
PEX7	ENST00000541292.6	c.116A>C	p.His39Pro	missense_variant, NMD_transcript_variant	1/11	5		ENSP00000441004
PEX7	ENST00000678593.1	c.116A>C	p.His39Pro	missense_variant, NMD_transcript_variant	1/8			ENSP00000503841

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.0000336 AC: 1 AN: 29772 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18632

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 8.29e-7 AC: 1 AN: 1206858 Hom.: 0 Cov.: 32 AF XY: 0.00000170 AC XY: 1 AN XY: 588104

Gnomad4 AFR exome AF: 0.0000413

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peroxisome biogenesis disorder 9B Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Rhizomelic chondrodysplasia punctata type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 21, 2024

Variant summary: PEX7 c.116A>C (p.His39Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 29772 control chromosomes (gnomAD). c.116A>C has been reported in the literature in an individual affected with Rhizomelic Chondrodysplasia Punctata Type 1 (Braverman_2002). This report does not provide unequivocal conclusions about association of the variant with Rhizomelic Chondrodysplasia Punctata Type 1. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in impaired import of PTS2 (Braverman_2002). The following publication has been ascertained in the context of this evaluation (PMID: 12325024). ClinVar contains an entry for this variant (Variation ID: 813362). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.27	.;T;D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.8	L;.;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D;D;T
Sift4G	Uncertain	0.042	D;T;D
Polyphen		0.87	.;.;P
Vest4		0.63
MutPred		0.82		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		1.0
MPC		0.40
ClinPred		0.26	T
GERP RS		5.3
Varity_R		0.67
gMVP		0.81

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: rs61753237; hg19: chr6-137143919;