7-92493122-C-T

Variant names:

• chr7-92493122-C-T
• rs1484321655
• NM_000466.3:c.3038G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000466.3(PEX1):​c.3038G>A​(p.Arg1013His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000692 in 1,589,650 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. R1013C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.69
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-92493123-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1069047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 7-92493122-C-T is Pathogenic according to our data. Variant chr7-92493122-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 551650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.3038G>A	p.Arg1013His	missense	Exon 20 of 24	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.2867G>A	p.Arg956His	missense	Exon 19 of 23	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.2414G>A	p.Arg805His	missense	Exon 20 of 24	NP_001269607.1	B4DER6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX1	ENST00000248633.9	TSL:1 MANE Select	c.3038G>A	p.Arg1013His	missense	Exon 20 of 24	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.2867G>A	p.Arg956His	missense	Exon 19 of 23	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.3092G>A	p.Arg1031His	missense	Exon 20 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151312 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000953

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 248816 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000626 AC: 9 AN: 1438338 Hom.: 0 Cov.: 26 AF XY: 0.00000419 AC XY: 3 AN XY: 715928

African (AFR) AF: 0.00 AC: 0 AN: 33114

American (AMR) AF: 0.00 AC: 0 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.0000775 AC: 2 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 39288

South Asian (SAS) AF: 0.00 AC: 0 AN: 83268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000548 AC: 6 AN: 1094430

Other (OTH) AF: 0.0000168 AC: 1 AN: 59426

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151312 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73834

African (AFR) AF: 0.00 AC: 0 AN: 41180

American (AMR) AF: 0.00 AC: 0 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.0000953 AC: 1 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67772

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Heimler syndrome 1 (1)
-	1	-	Peroxisome biogenesis disorder 1A (Zellweger) (1)
1	-	-	Peroxisome biogenesis disorder 1B;C4721541:Peroxisome biogenesis disorder 1A (Zellweger) (1)
1	-	-	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.96		Loss of disorder (P = 0.1357)
MVP		0.98
MPC		0.75
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.82
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1484321655; hg19: chr7-92122436; COSMIC: COSV50403605; COSMIC: COSV50403605;