chr6-136822781-A-C

Variant names:

• chr6-136822781-A-C
• rs61753237
• NM_000288.4:c.116A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000288.4(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 NM_000288.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.25
• Publications: 1 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: Uncertain_significance. The variant received 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 VariationId is 813362.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000288.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX7	NM_000288.4	MANE Select	c.116A>C	p.His39Pro	missense	Exon 1 of 10	NP_000279.1
	PEX7	NM_001410945.1		c.-583A>C		upstream_gene	N/A	NP_001397874.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX7	ENST00000318471.5	TSL:1 MANE Select	c.116A>C	p.His39Pro	missense	Exon 1 of 10	ENSP00000315680.3
	PEX7	ENST00000367756.8	TSL:3	c.116A>C	p.His39Pro	missense	Exon 1 of 4	ENSP00000356730.4
	PEX7	ENST00000541292.6	TSL:5	n.116A>C		non_coding_transcript_exon	Exon 1 of 11	ENSP00000441004.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.0000336 AC: 1 AN: 29772 AF XY: 0.00

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 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

African (AFR) AF: 0.0000413 AC: 1 AN: 24200

American (AMR) AF: 0.00 AC: 0 AN: 12708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18222

East Asian (EAS) AF: 0.00 AC: 0 AN: 26564

South Asian (SAS) AF: 0.00 AC: 0 AN: 50924

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3466

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 992112

Other (OTH) AF: 0.00 AC: 0 AN: 49218

GnomAD4 genome Cov.: 35

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Peroxisome biogenesis disorder 9B (2)
-	1	-	not specified (1)
1	-	-	Rhizomelic chondrodysplasia punctata type 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.8	L
PhyloP100		7.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.042	D
Polyphen		0.87	P
Vest4		0.63
MutPred		0.82		Gain of sheet (P = 0.0149)
MVP		1.0
MPC		0.40
ClinPred		0.26	T
GERP RS		5.3
PromoterAI		0.0028	Neutral
Varity_R		0.67
gMVP		0.81
Mutation Taster		=15/85	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: rs61753237; hg19: chr6-137143919;