chr6-136822705-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000288.4(PEX7):​c.40A>G​(p.Thr14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000293 in 1,365,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000029 (0 hom.)
• Consequence: PEX7 NM_000288.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.789
• Publications: 0 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 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=0.250368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX7	NM_000288.4	c.40A>G	p.Thr14Ala	missense_variant	Exon 1 of 10	ENST00000318471.5	NP_000279.1
PEX7	XM_006715502.3	c.40A>G	p.Thr14Ala	missense_variant	Exon 1 of 7		XP_006715565.1
PEX7	XM_047418874.1	c.40A>G	p.Thr14Ala	missense_variant	Exon 1 of 6		XP_047274830.1
PEX7	NM_001410945.1	c.-659A>G		upstream_gene_variant			NP_001397874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX7	ENST00000318471.5	c.40A>G	p.Thr14Ala	missense_variant	Exon 1 of 10	1	NM_000288.4	ENSP00000315680.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000293 AC: 4 AN: 1365516 Hom.: 0 Cov.: 33 AF XY: 0.00000445 AC XY: 3 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: 0.00000373 AC: 4 AN: 1071604

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

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.24	.;T;D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.8	L;.;L
PhyloP100		0.79
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.2	N;D;N
REVEL	Benign	0.18
Sift	Uncertain	0.026	D;D;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.0030	.;.;B
Vest4		0.076
MutPred		0.46		Loss of phosphorylation at T14 (P = 0.033);Loss of phosphorylation at T14 (P = 0.033);Loss of phosphorylation at T14 (P = 0.033);
MVP		0.97
MPC		0.14
ClinPred		0.18	T
GERP RS		2.1
PromoterAI		-0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.10
gMVP		0.42
Mutation Taster		=56/44	polymorphism

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;