rs750722718

Variant names:

• chr7-92487477-G-T
• rs750722718
• NM_000466.3:c.3832C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000466.3(PEX1):​c.3832C>A​(p.Gln1278Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PEX1 NM_000466.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39948368).

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.3832C>A	p.Gln1278Lys	missense	Exon 24 of 24	NP_000457.1
	PEX1	NM_001282677.2		c.3661C>A	p.Gln1221Lys	missense	Exon 23 of 23	NP_001269606.1
	PEX1	NM_001282678.2		c.3208C>A	p.Gln1070Lys	missense	Exon 24 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.3832C>A	p.Gln1278Lys	missense	Exon 24 of 24	ENSP00000248633.4
	PEX1	ENST00000428214.5	TSL:1	c.3661C>A	p.Gln1221Lys	missense	Exon 23 of 23	ENSP00000394413.1
	PEX1	ENST00000951788.1		c.3886C>A	p.Gln1296Lys	missense	Exon 24 of 24	ENSP00000621847.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248236 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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435410 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 715240

African (AFR) AF: 0.00 AC: 0 AN: 32984

American (AMR) AF: 0.00 AC: 0 AN: 43876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39270

South Asian (SAS) AF: 0.00 AC: 0 AN: 84038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091278

Other (OTH) AF: 0.0000168 AC: 1 AN: 59398

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.40	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.42
MutPred		0.25		Gain of methylation at Q1278 (P = 0.025)
MVP		0.95
MPC		0.76
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.69
gMVP		0.50
Mutation Taster		=61/39	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: rs750722718; hg19: chr7-92116791;