NM_002617.4:c.913-4G>A

Variant names:

• chr1-2405838-C-T
• rs11586985
• NM_002617.4:c.913-4G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002617.4(PEX10):​c.913-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,586,640 control chromosomes in the GnomAD database, including 9,839 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (809 hom., cov: 34)
  • Exomes 𝑓: 0.11 (9030 hom.)
• Consequence: PEX10 NM_002617.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004033
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.60
• Publications: 12 publications found

Genes affected

PEX10 (HGNC:8851): (peroxisomal biogenesis factor 10) This gene encodes a protein involved in import of peroxisomal matrix proteins. This protein localizes to the peroxisomal membrane. Mutations in this gene result in phenotypes within the Zellweger spectrum of peroxisomal biogenesis disorders, ranging from neonatal adrenoleukodystrophy to Zellweger syndrome. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

PEX10 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 6A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 6B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal recessive ataxia due to PEX10 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-2405838-C-T is Benign according to our data. Variant chr1-2405838-C-T is described in ClinVar as Benign. ClinVar VariationId is 262791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002617.4. 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
	PEX10	NM_002617.4	MANE Select	c.913-4G>A		splice_region intron	N/A	NP_002608.1
	PEX10	NM_153818.2		c.973-4G>A		splice_region intron	N/A	NP_722540.1
	PEX10	NM_001374425.1		c.970-4G>A		splice_region intron	N/A	NP_001361354.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX10	ENST00000447513.7	TSL:1 MANE Select	c.913-4G>A		splice_region intron	N/A	ENSP00000407922.2
	PEX10	ENST00000288774.8	TSL:1	c.973-4G>A		splice_region intron	N/A	ENSP00000288774.3
	PEX10	ENST00000874692.1		c.970-4G>A		splice_region intron	N/A	ENSP00000544751.1

Frequencies

GnomAD3 genomes AF: 0.0878 AC: 13368 AN: 152218 Hom.: 808 Cov.: 34

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0801

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.105 AC: 21178 AN: 201770 AF XY: 0.108

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.0584

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.110 AC: 157972 AN: 1434304 Hom.: 9030 Cov.: 32 AF XY: 0.111 AC XY: 78588 AN XY: 711104

African (AFR) AF: 0.0212 AC: 696 AN: 32858

American (AMR) AF: 0.0617 AC: 2544 AN: 41220

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3062 AN: 25622

East Asian (EAS) AF: 0.0914 AC: 3487 AN: 38138

South Asian (SAS) AF: 0.109 AC: 8985 AN: 82292

European-Finnish (FIN) AF: 0.128 AC: 6419 AN: 50236

Middle Eastern (MID) AF: 0.200 AC: 1135 AN: 5664

European-Non Finnish (NFE) AF: 0.114 AC: 124988 AN: 1098884

Other (OTH) AF: 0.112 AC: 6656 AN: 59390

GnomAD4 genome AF: 0.0878 AC: 13368 AN: 152336 Hom.: 809 Cov.: 34 AF XY: 0.0888 AC XY: 6617 AN XY: 74498

African (AFR) AF: 0.0221 AC: 920 AN: 41584

American (AMR) AF: 0.0799 AC: 1223 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 441 AN: 3470

East Asian (EAS) AF: 0.117 AC: 608 AN: 5188

South Asian (SAS) AF: 0.101 AC: 489 AN: 4828

European-Finnish (FIN) AF: 0.127 AC: 1347 AN: 10616

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 7995 AN: 68024

Other (OTH) AF: 0.111 AC: 234 AN: 2114

Alfa AF: 0.0815 Hom.: 249

Bravo AF: 0.0813

Asia WGS AF: 0.110 AC: 381 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Peroxisome biogenesis disorder 6A (Zellweger) (2)
-	-	1	not specified (1)
-	-	1	Peroxisome biogenesis disorder 6B (1)
-	-	1	Peroxisome biogenesis disorder, complementation group 7 (1)
-	-	1	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.20
DANN	Benign	0.61
PhyloP100		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
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: rs11586985; hg19: chr1-2337277; COSMIC: COSV56580725; COSMIC: COSV56580725;