NM_004813.4:c.*376G>C

Variant names:

• chr11-45909878-C-G
• rs143868125
• NM_004813.4:c.*376G>C

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.*376G>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 0.00747 in 597,212 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (100 hom., cov: 34)
  • Exomes 𝑓: 0.0032 (31 hom.)
• Consequence: PEX16 NM_004813.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.510
• Publications: 0 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=-0.89).
• BP6: Variant 11-45909878-C-G is Benign according to our data. Variant chr11-45909878-C-G is described in ClinVar as [Benign]. Clinvar id is 304776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX16	NM_004813.4	c.*376G>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	ENST00000378750.10	c.*376G>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_004813.4	ENSP00000368024.5
PEX16	ENST00000241041.7	c.*211G>C		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000241041.3

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3025 AN: 152202 Hom.: 101 Cov.: 34

Gnomad AFR AF: 0.0677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.00323 AC: 1436 AN: 444892 Hom.: 31 Cov.: 4 AF XY: 0.00287 AC XY: 674 AN XY: 234610

African (AFR) AF: 0.0697 AC: 872 AN: 12510

American (AMR) AF: 0.00577 AC: 118 AN: 20464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13688

East Asian (EAS) AF: 0.0000328 AC: 1 AN: 30534

South Asian (SAS) AF: 0.00394 AC: 185 AN: 47012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28522

Middle Eastern (MID) AF: 0.00310 AC: 6 AN: 1936

European-Non Finnish (NFE) AF: 0.000306 AC: 81 AN: 264660

Other (OTH) AF: 0.00677 AC: 173 AN: 25566

GnomAD4 genome AF: 0.0199 AC: 3025 AN: 152320 Hom.: 100 Cov.: 34 AF XY: 0.0192 AC XY: 1432 AN XY: 74482

African (AFR) AF: 0.0675 AC: 2806 AN: 41556

American (AMR) AF: 0.00960 AC: 147 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68026

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0232

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 21, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.89
CADD	Benign	0.33
DANN	Benign	0.54
PhyloP100		-0.51
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: rs143868125; hg19: chr11-45931429;