rs34154371

Variant names:

• chr1-2406576-T-C
• rs34154371
• NM_002617.4:c.820A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-2406576-T-C
• chr1-2406576-T-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002617.4(PEX10):​c.820A>G​(p.Thr274Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,613,202 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T274I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 33)
  • Exomes 𝑓: 0.023 (465 hom.)
• Consequence: PEX10 NM_002617.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.96
• Publications: 17 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: Myriad Women’s Health, Ambry Genetics, G2P
• peroxisome biogenesis disorder 6B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, 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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_002617.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0106090605).
• BP6: Variant 1-2406576-T-C is Benign according to our data. Variant chr1-2406576-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197887.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 = 0.0187 (2850/152162) while in subpopulation NFE AF = 0.0264 (1793/67986). AF 95% confidence interval is 0.0254. There are 42 homozygotes in GnomAd4. There are 1323 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

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.820A>G	p.Thr274Ala	missense	Exon 5 of 6	NP_002608.1	O60683-1
	PEX10	NM_153818.2		c.880A>G	p.Thr294Ala	missense	Exon 5 of 6	NP_722540.1	O60683-2
	PEX10	NM_001374425.1		c.877A>G	p.Thr293Ala	missense	Exon 5 of 6	NP_001361354.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX10	ENST00000447513.7	TSL:1 MANE Select	c.820A>G	p.Thr274Ala	missense	Exon 5 of 6	ENSP00000407922.2	O60683-1
	PEX10	ENST00000288774.8	TSL:1	c.880A>G	p.Thr294Ala	missense	Exon 5 of 6	ENSP00000288774.3	O60683-2
	PEX10	ENST00000874692.1		c.877A>G	p.Thr293Ala	missense	Exon 5 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2851 AN: 152044 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.00473

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0842

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00975

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0203 AC: 5069 AN: 250264 AF XY: 0.0205

Gnomad AFR exome AF: 0.00428

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0814

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0286

GnomAD4 exome AF: 0.0231 AC: 33805 AN: 1461040 Hom.: 465 Cov.: 34 AF XY: 0.0230 AC XY: 16719 AN XY: 726848

African (AFR) AF: 0.00349 AC: 117 AN: 33478

American (AMR) AF: 0.0142 AC: 633 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 2152 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0100 AC: 865 AN: 86252

European-Finnish (FIN) AF: 0.0140 AC: 739 AN: 52656

Middle Eastern (MID) AF: 0.0260 AC: 150 AN: 5766

European-Non Finnish (NFE) AF: 0.0248 AC: 27590 AN: 1111954

Other (OTH) AF: 0.0258 AC: 1557 AN: 60388

GnomAD4 genome AF: 0.0187 AC: 2850 AN: 152162 Hom.: 42 Cov.: 33 AF XY: 0.0178 AC XY: 1323 AN XY: 74384

African (AFR) AF: 0.00472 AC: 196 AN: 41522

American (AMR) AF: 0.0186 AC: 285 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0842 AC: 292 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00976 AC: 47 AN: 4816

European-Finnish (FIN) AF: 0.0149 AC: 158 AN: 10604

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0264 AC: 1793 AN: 67986

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

Alfa AF: 0.0247 Hom.: 85

Bravo AF: 0.0182

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0286 AC: 246

ExAC AF: 0.0188 AC: 2277

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0310

EpiControl AF: 0.0271

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Peroxisome biogenesis disorder 6A (Zellweger) (2)
-	-	1	Peroxisome biogenesis disorder, complementation group 7 (1)
-	-	1	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	-0.56	N
PhyloP100		3.0
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.12	T
Sift4G	Benign	0.16	T
Polyphen		0.95	P
Vest4		0.47
MPC		0.19
ClinPred		0.020	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.44
Mutation Taster		=82/18	polymorphism (auto)

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: rs34154371; hg19: chr1-2338015; COSMIC: COSV56580904; COSMIC: COSV56580904;