11-45910079-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004813.4(PEX16):c.*175C>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 0.000628 in 1,608,722 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00064 (2 hom.)
• Consequence: PEX16 NM_004813.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.134

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-45910079-G-T is Benign according to our data. Variant chr11-45910079-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 879237.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr11-45910079-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000525 (80/152238) while in subpopulation NFE AF= 0.00103 (70/68042). AF 95% confidence interval is 0.000834. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX16	NM_004813.4	c.*175C>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.*175C>A		3_prime_UTR_variant	11/11	1	NM_004813.4	P1
PEX16	ENST00000241041.7	c.*10C>A		3_prime_UTR_variant	11/11	1

Frequencies

GnomAD3 genomes AF: 0.000525 AC: 80 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000545 AC: 136 AN: 249680 Hom.: 1 AF XY: 0.000481 AC XY: 65 AN XY: 135220

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000897

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000192

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000639 AC: 930 AN: 1456484 Hom.: 2 Cov.: 31 AF XY: 0.000611 AC XY: 443 AN XY: 724726

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000248

Gnomad4 NFE exome AF: 0.000769

Gnomad4 OTH exome AF: 0.000482

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000471 AC XY: 35 AN XY: 74376

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000792 Hom.: 0

Bravo AF: 0.000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

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. -

PEX16-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.9
Dann	Benign	0.69

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs375099703; hg19: chr11-45931630; COSMIC: COSV99571756; COSMIC: COSV99571756;