rs79435202

Variant names:

• chr11-45910096-T-G
• rs79435202
• ENST00000241041.7:c.1034A>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_004813.4(PEX16):​c.*158A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,611,204 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (35 hom.)
• Consequence: PEX16 NM_004813.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.937
• Publications: 4 publications found

Genes affected

PEX16 (HGNC:8857): (peroxisomal biogenesis factor 16) The protein encoded by this gene is an integral peroxisomal membrane protein. An inactivating nonsense mutation localized to this gene was observed in a patient with Zellweger syndrome of the complementation group CGD/CG9. Expression of this gene product morphologically and biochemically restores the formation of new peroxisomes, suggesting a role in peroxisome organization and biogenesis. Alternative splicing has been observed for this gene and two variants have been described. [provided by RefSeq, Jul 2008]

PEX16 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 8A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
• peroxisome biogenesis disorder 8B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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 (MetaRNN=0.002622664).
• BP6: Variant 11-45910096-T-G is Benign according to our data. Variant chr11-45910096-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 304783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0134 (2037/152226) while in subpopulation AFR AF = 0.045 (1870/41536). AF 95% confidence interval is 0.0433. There are 40 homozygotes in GnomAd4. There are 951 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX16	NM_004813.4	c.*158A>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000378750.10	NP_004804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX16	ENST00000241041.7	c.1034A>C	p.His345Pro	missense_variant	Exon 11 of 11	1		ENSP00000241041.3
PEX16	ENST00000378750.10	c.*158A>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_004813.4	ENSP00000368024.5
PEX16	ENST00000532681.5	c.*158A>C		downstream_gene_variant		3		ENSP00000434654.1
PEX16	ENST00000523721.2	n.*74A>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2028 AN: 152108 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00403 AC: 1008 AN: 250066 AF XY: 0.00290

Gnomad AFR exome AF: 0.0470

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000743

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00191 AC: 2785 AN: 1458978 Hom.: 35 Cov.: 32 AF XY: 0.00174 AC XY: 1261 AN XY: 725812

African (AFR) AF: 0.0472 AC: 1576 AN: 33408

American (AMR) AF: 0.00432 AC: 193 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52786

Middle Eastern (MID) AF: 0.00772 AC: 32 AN: 4146

European-Non Finnish (NFE) AF: 0.000618 AC: 687 AN: 1111730

Other (OTH) AF: 0.00447 AC: 269 AN: 60204

GnomAD4 genome AF: 0.0134 AC: 2037 AN: 152226 Hom.: 40 Cov.: 33 AF XY: 0.0128 AC XY: 951 AN XY: 74434

African (AFR) AF: 0.0450 AC: 1870 AN: 41536

American (AMR) AF: 0.00602 AC: 92 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 67994

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.00340 Hom.: 10

Bravo AF: 0.0152

ESP6500AA AF: 0.0350 AC: 154

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00449 AC: 545

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 18, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 8A (Zellweger) Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.1
DANN	Benign	0.37
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00071	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.94
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.049
Sift	Benign	0.40	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.11
MPC		0.55
ClinPred		0.00079	T
GERP RS		2.9
gMVP		0.56
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs79435202; hg19: chr11-45931647;