Genetic Variant NM_002617.4:c.291A>G (chr1-2408761-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002617.4(PEX10):c.291A>G(p.Thr97Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,613,626 control chromosomes in the GnomAD database, including 513,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T97T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.74 ( 42754 hom., cov: 33)

Exomes 𝑓: 0.80 ( 470883 hom. )

Consequence

PEX10
NM_002617.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -6.52

Publications

27 publications found

Variant links:

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

PEX10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.04).

BP6

Variant 1-2408761-T-C is Benign according to our data. Variant chr1-2408761-T-C is described in ClinVar as Benign. ClinVar VariationId is 129884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.52 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.806 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX10	NM_002617.4	MANE Select	c.291A>G	p.Thr97Thr	synonymous	Exon 3 of 6	NP_002608.1	O60683-1
PEX10	NM_153818.2		c.291A>G	p.Thr97Thr	synonymous	Exon 3 of 6	NP_722540.1	O60683-2
PEX10	NM_001374425.1		c.291A>G	p.Thr97Thr	synonymous	Exon 3 of 6	NP_001361354.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEX10	ENST00000447513.7	TSL:1 MANE Select	c.291A>G	p.Thr97Thr	synonymous	Exon 3 of 6	ENSP00000407922.2	O60683-1
PEX10	ENST00000288774.8	TSL:1	c.291A>G	p.Thr97Thr	synonymous	Exon 3 of 6	ENSP00000288774.3	O60683-2
PEX10	ENST00000874692.1		c.291A>G	p.Thr97Thr	synonymous	Exon 3 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes

AF:

0.743

AC:

112937

AN:

151974

Hom.:

42746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.599

Gnomad AMI

AF:

0.861

Gnomad AMR

AF:

0.770

Gnomad ASJ

AF:

0.826

Gnomad EAS

AF:

0.726

Gnomad SAS

AF:

0.732

Gnomad FIN

AF:

0.804

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.812

Gnomad OTH

AF:

0.741

GnomAD2 exomes

AF:

0.773

AC:

193696

AN:

250422

AF XY:

0.776

show subpopulations

Gnomad AFR exome

AF:

0.592

Gnomad AMR exome

AF:

0.771

Gnomad ASJ exome

AF:

0.824

Gnomad EAS exome

AF:

0.718

Gnomad FIN exome

AF:

0.808

Gnomad NFE exome

AF:

0.811

Gnomad OTH exome

AF:

0.777

GnomAD4 exome

AF:

0.801

AC:

1171196

AN:

1461534

Hom.:

470883

Cov.:

AF XY:

0.800

AC XY:

581559

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.596

AC:

19953

AN:

33472

American (AMR)

AF:

0.773

AC:

34556

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.823

AC:

21505

AN:

26120

East Asian (EAS)

AF:

0.763

AC:

30284

AN:

39686

South Asian (SAS)

AF:

0.728

AC:

62786

AN:

86246

European-Finnish (FIN)

AF:

0.803

AC:

42797

AN:

53316

Middle Eastern (MID)

AF:

0.707

AC:

4079

AN:

5768

European-Non Finnish (NFE)

AF:

0.817

AC:

908139

AN:

1111848

Other (OTH)

AF:

0.780

AC:

47097

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

15000

29999

44999

59998

74998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20868

41736

62604

83472

104340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.743

AC:

112971

AN:

152092

Hom.:

42754

Cov.:

AF XY:

0.742

AC XY:

55167

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.599

AC:

24812

AN:

41456

American (AMR)

AF:

0.770

AC:

11780

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.826

AC:

2869

AN:

3472

East Asian (EAS)

AF:

0.725

AC:

3742

AN:

5162

South Asian (SAS)

AF:

0.731

AC:

3526

AN:

4822

European-Finnish (FIN)

AF:

0.804

AC:

8528

AN:

10606

Middle Eastern (MID)

AF:

0.653

AC:

192

AN:

294

European-Non Finnish (NFE)

AF:

0.812

AC:

55189

AN:

67968

Other (OTH)

AF:

0.734

AC:

1551

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1466

2931

4397

5862

7328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.785

Hom.:

23910

Bravo

AF:

0.735

Asia WGS

AF:

0.678

AC:

2359

AN:

3478

EpiCase

AF:

0.807

EpiControl

AF:

0.805

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Peroxisome biogenesis disorder 6A (Zellweger) (2)

Peroxisome biogenesis disorder 6B (1)

Peroxisome biogenesis disorder, complementation group 7 (1)

Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.017

(source)

DANN

Benign

0.23

PhyloP100

-6.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over