rs61753233

Variant names:

• chr6-136822705-A-C
• rs61753233
• NM_000288.4:c.40A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-136822705-A-C
• chr6-136822705-A-G
• chr6-136822705-A-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T14M) has been classified as Uncertain significance.

• 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
• Publications: 4 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 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/Likely_pathogenic. ClinVar VariationId is 7790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX7	NM_000288.4	c.40A>C	p.Thr14Pro	missense_variant	Exon 1 of 10	ENST00000318471.5	NP_000279.1
PEX7	XM_006715502.3	c.40A>C	p.Thr14Pro	missense_variant	Exon 1 of 7		XP_006715565.1
PEX7	XM_047418874.1	c.40A>C	p.Thr14Pro	missense_variant	Exon 1 of 6		XP_047274830.1
PEX7	NM_001410945.1	c.-659A>C		upstream_gene_variant			NP_001397874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5	c.40A>C	p.Thr14Pro	missense_variant	Exon 1 of 10	1	NM_000288.4	ENSP00000315680.3

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

African (AFR) AF: 0.00 AC: 0 AN: 28836

American (AMR) AF: 0.00 AC: 0 AN: 34364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24456

East Asian (EAS) AF: 0.00 AC: 0 AN: 33696

South Asian (SAS) AF: 0.00 AC: 0 AN: 77858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.0000168 AC: 18 AN: 1071604

Other (OTH) AF: 0.00 AC: 0 AN: 56824

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

Oct 16, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rhizomelic chondrodysplasia punctata type 1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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
PhyloP100		0.79
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
PromoterAI		-0.0042	Neutral
Varity_R		0.43
gMVP		0.75
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs61753233; hg19: chr6-137143843;