11-45909816-G-A

Variant names:

• chr11-45909816-G-A
• rs2280328
• NM_004813.4:c.*438C>T

Variant summary

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

The NM_004813.4(PEX16):​c.*438C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 530,004 control chromosomes in the GnomAD database, including 214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (109 hom., cov: 34)
  • Exomes 𝑓: 0.010 (105 hom.)
• Consequence: PEX16 NM_004813.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.562
• Publications: 2 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 (BayesDel_noAF=-0.9).
• BP6: Variant 11-45909816-G-A is Benign according to our data. Variant chr11-45909816-G-A is described in ClinVar as [Benign]. Clinvar id is 304775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX16	NM_004813.4	c.*438C>T		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	ENST00000378750.10	c.*438C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_004813.4	ENSP00000368024.5
PEX16	ENST00000241041.7	c.*273C>T		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000241041.3

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3317 AN: 152228 Hom.: 109 Cov.: 34

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0104 AC: 3936 AN: 377658 Hom.: 105 Cov.: 0 AF XY: 0.0117 AC XY: 2314 AN XY: 197708

African (AFR) AF: 0.0674 AC: 748 AN: 11100

American (AMR) AF: 0.00436 AC: 71 AN: 16290

Ashkenazi Jewish (ASJ) AF: 0.00229 AC: 27 AN: 11816

East Asian (EAS) AF: 0.0314 AC: 804 AN: 25574

South Asian (SAS) AF: 0.0425 AC: 1785 AN: 42022

European-Finnish (FIN) AF: 0.00345 AC: 80 AN: 23186

Middle Eastern (MID) AF: 0.00531 AC: 9 AN: 1696

European-Non Finnish (NFE) AF: 0.000724 AC: 162 AN: 223882

Other (OTH) AF: 0.0113 AC: 250 AN: 22092

GnomAD4 genome AF: 0.0218 AC: 3314 AN: 152346 Hom.: 109 Cov.: 34 AF XY: 0.0220 AC XY: 1640 AN XY: 74498

African (AFR) AF: 0.0636 AC: 2644 AN: 41576

American (AMR) AF: 0.00817 AC: 125 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.0318 AC: 165 AN: 5188

South Asian (SAS) AF: 0.0503 AC: 243 AN: 4832

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68024

Other (OTH) AF: 0.0194 AC: 41 AN: 2116

Alfa AF: 0.0159 Hom.: 19

Bravo AF: 0.0231

Asia WGS AF: 0.0870 AC: 300 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 8A (Zellweger) Benign:1

Jan 13, 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_noAF	Benign	-0.90
CADD	Benign	0.81
DANN	Benign	0.72
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2280328; hg19: chr11-45931367;