NM_000466.3:c.3750G>A

Variant names:

• chr7-92489310-C-T
• rs863225085
• NM_000466.3:c.3750G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000466.3(PEX1):​c.3750G>A​(p.Trp1250*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX1 NM_000466.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.36
• Publications: 4 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]

ENSG00000244055 (HGNC:):

GATAD1 (HGNC:29941): (GATA zinc finger domain containing 1) The protein encoded by this gene contains a zinc finger at the N-terminus, and is thought to bind to a histone modification site that regulates gene expression. Mutations in this gene have been associated with autosomal recessive dilated cardiomyopathy. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

GATAD1 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 2B

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0265 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-92489310-C-T is Pathogenic according to our data. Variant chr7-92489310-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217431.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000466.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	NM_000466.3	MANE Select	c.3750G>A	p.Trp1250*	stop_gained	Exon 23 of 24	NP_000457.1
	PEX1	NM_001282677.2		c.3579G>A	p.Trp1193*	stop_gained	Exon 22 of 23	NP_001269606.1
	PEX1	NM_001282678.2		c.3126G>A	p.Trp1042*	stop_gained	Exon 23 of 24	NP_001269607.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	ENST00000248633.9	TSL:1 MANE Select	c.3750G>A	p.Trp1250*	stop_gained	Exon 23 of 24	ENSP00000248633.4
	PEX1	ENST00000428214.5	TSL:1	c.3579G>A	p.Trp1193*	stop_gained	Exon 22 of 23	ENSP00000394413.1
	PEX1	ENST00000951788.1		c.3804G>A	p.Trp1268*	stop_gained	Exon 23 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Heimler syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	0.99
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.4
Vest4		0.74
GERP RS		4.4
Mutation Taster		=1/199	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: rs863225085; hg19: chr7-92118624;