1-2406784-C-G

Variant names:

• chr1-2406784-C-G
• rs61736380
• NM_002617.4:c.712G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_002617.4(PEX10):​c.712G>C​(p.Gly238Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,610,650 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G238S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: PEX10 NM_002617.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 0.469
• Publications: 5 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: G2P, Ambry Genetics, 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010670394).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00138 (210/152332) while in subpopulation NFE AF = 0.00209 (142/68030). AF 95% confidence interval is 0.00181. There are 1 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 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.712G>C	p.Gly238Arg	missense	Exon 4 of 6	NP_002608.1
	PEX10	NM_153818.2		c.772G>C	p.Gly258Arg	missense	Exon 4 of 6	NP_722540.1
	PEX10	NM_001374425.1		c.769G>C	p.Gly257Arg	missense	Exon 4 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.712G>C	p.Gly238Arg	missense	Exon 4 of 6	ENSP00000407922.2
	PEX10	ENST00000288774.8	TSL:1	c.772G>C	p.Gly258Arg	missense	Exon 4 of 6	ENSP00000288774.3
	PEX10	ENST00000874692.1		c.769G>C	p.Gly257Arg	missense	Exon 4 of 6	ENSP00000544751.1

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152214 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00129 AC: 312 AN: 241814 AF XY: 0.00136

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00194

Gnomad EAS exome AF: 0.0000555

Gnomad FIN exome AF: 0.000196

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00204

GnomAD4 exome AF: 0.00113 AC: 1643 AN: 1458318 Hom.: 3 Cov.: 35 AF XY: 0.00116 AC XY: 844 AN XY: 725264

African (AFR) AF: 0.000179 AC: 6 AN: 33446

American (AMR) AF: 0.00142 AC: 63 AN: 44382

Ashkenazi Jewish (ASJ) AF: 0.00215 AC: 56 AN: 26058

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39604

South Asian (SAS) AF: 0.000513 AC: 44 AN: 85784

European-Finnish (FIN) AF: 0.000326 AC: 17 AN: 52068

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5762

European-Non Finnish (NFE) AF: 0.00119 AC: 1318 AN: 1110990

Other (OTH) AF: 0.00153 AC: 92 AN: 60224

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152332 Hom.: 1 Cov.: 34 AF XY: 0.00158 AC XY: 118 AN XY: 74484

African (AFR) AF: 0.000192 AC: 8 AN: 41570

American (AMR) AF: 0.000914 AC: 14 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00209 AC: 142 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00136

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00116 AC: 141

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	Peroxisome biogenesis disorder 6A (Zellweger) (2)
-	1	-	Peroxisome biogenesis disorder 6A (Zellweger);C3553948:Peroxisome biogenesis disorder 6B (1)
-	-	1	Peroxisome biogenesis disorder, complementation group 7 (1)
-	-	1	PEX10-related disorder (1)
-	-	1	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.47
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.34
Sift	Benign	0.19	T
Sift4G	Benign	0.11	T
Polyphen		0.82	P
Vest4		0.31
MVP		0.84
MPC		0.22
ClinPred		0.038	T
GERP RS		-0.23
Varity_R		0.058
gMVP		0.57
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61736380; hg19: chr1-2338223;