NM_000466.3:c.1671-7T>C

Variant names:

• chr7-92507133-A-G
• rs74519968
• NM_000466.3:c.1671-7T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000466.3(PEX1):​c.1671-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,612,494 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 32)
  • Exomes 𝑓: 0.016 (208 hom.)
• Consequence: PEX1 NM_000466.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001180
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.21
• Publications: 2 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: Ambry Genetics, Myriad Women’s Health
• Heimler syndrome 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 7-92507133-A-G is Benign according to our data. Variant chr7-92507133-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1926/152328) while in subpopulation NFE AF = 0.0201 (1368/68024). AF 95% confidence interval is 0.0192. There are 22 homozygotes in GnomAd4. There are 868 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

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.1671-7T>C		splice_region intron	N/A	NP_000457.1	O43933-1
	PEX1	NM_001282677.2		c.1671-7T>C		splice_region intron	N/A	NP_001269606.1	A0A0C4DG33
	PEX1	NM_001282678.2		c.1047-7T>C		splice_region intron	N/A	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.1671-7T>C		splice_region intron	N/A	ENSP00000248633.4	O43933-1
	PEX1	ENST00000428214.5	TSL:1	c.1671-7T>C		splice_region intron	N/A	ENSP00000394413.1	A0A0C4DG33
	PEX1	ENST00000951788.1		c.1671-7T>C		splice_region intron	N/A	ENSP00000621847.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1930 AN: 152210 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0119 AC: 2981 AN: 250794 AF XY: 0.0115

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.00953

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00847

Gnomad NFE exome AF: 0.0183

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0159 AC: 23150 AN: 1460166 Hom.: 208 Cov.: 30 AF XY: 0.0156 AC XY: 11304 AN XY: 726534

African (AFR) AF: 0.00275 AC: 92 AN: 33456

American (AMR) AF: 0.00977 AC: 437 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0186 AC: 487 AN: 26118

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39668

South Asian (SAS) AF: 0.00251 AC: 216 AN: 86226

European-Finnish (FIN) AF: 0.00909 AC: 485 AN: 53378

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5764

European-Non Finnish (NFE) AF: 0.0185 AC: 20577 AN: 1110524

Other (OTH) AF: 0.0138 AC: 833 AN: 60318

GnomAD4 genome AF: 0.0126 AC: 1926 AN: 152328 Hom.: 22 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74488

African (AFR) AF: 0.00394 AC: 164 AN: 41576

American (AMR) AF: 0.0119 AC: 182 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00763 AC: 81 AN: 10622

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0201 AC: 1368 AN: 68024

Other (OTH) AF: 0.0185 AC: 39 AN: 2110

Alfa AF: 0.0169 Hom.: 15

Bravo AF: 0.0121

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0173

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	2	Zellweger spectrum disorders (2)
-	-	1	Peroxisome biogenesis disorder 1A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.7
DANN	Benign	0.65
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0020
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: rs74519968; hg19: chr7-92136447; COSMIC: COSV104373556;