11-45909878-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_004813.4(PEX16):c.*376G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 597,212 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0022 (11 hom.)
• Consequence: PEX16 NM_004813.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.510

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00125 (190/152324) while in subpopulation EAS AF= 0.0147 (76/5186). AF 95% confidence interval is 0.012. There are 0 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX16	NM_004813.4	c.*376G>A		3_prime_UTR_variant	11/11	ENST00000378750.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX16	ENST00000378750.10	c.*376G>A		3_prime_UTR_variant	11/11	1	NM_004813.4	P1
PEX16	ENST00000241041.7	c.*211G>A		3_prime_UTR_variant	11/11	1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 192 AN: 152206 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00536

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00216 AC: 962 AN: 444888 Hom.: 11 Cov.: 4 AF XY: 0.00217 AC XY: 508 AN XY: 234606

Gnomad4 AFR exome AF: 0.000160

Gnomad4 AMR exome AF: 0.000684

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0172

Gnomad4 SAS exome AF: 0.00194

Gnomad4 FIN exome AF: 0.00529

Gnomad4 NFE exome AF: 0.000529

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152324 Hom.: 0 Cov.: 34 AF XY: 0.00161 AC XY: 120 AN XY: 74484

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0147

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00536

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.00117

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 8A (Zellweger) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.55
Dann	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs143868125; hg19: chr11-45931429;