7-92499808-G-C

Variant names:

• chr7-92499808-G-C
• rs61750422
• NM_000466.3:c.2614C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000466.3(PEX1):​c.2614C>G​(p.Arg872Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R872Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.49
• Publications: 6 publications found

Genes affected

PEX1 (HGNC:8850): (peroxisomal biogenesis factor 1) This gene encodes a member of the AAA ATPase family, a large group of ATPases associated with diverse cellular activities. This protein is cytoplasmic but is often anchored to a peroxisomal membrane where it forms a heteromeric complex and plays a role in the import of proteins into peroxisomes and peroxisome biogenesis. Mutations in this gene have been associated with complementation group 1 peroxisomal disorders such as neonatal adrenoleukodystrophy, infantile Refsum disease, and Zellweger syndrome. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2013]

PEX1 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 1A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, Ambry Genetics
• Heimler syndrome 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics
• peroxisome biogenesis disorder 1B

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000244055 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX1	NM_000466.3	c.2614C>G	p.Arg872Gly	missense_variant	Exon 16 of 24	ENST00000248633.9	NP_000457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX1	ENST00000248633.9	c.2614C>G	p.Arg872Gly	missense_variant	Exon 16 of 24	1	NM_000466.3	ENSP00000248633.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	0.0	.;M;.
PhyloP100		6.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.85
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.87
gMVP		0.96
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs61750422; hg19: chr7-92129122;