11-45910189-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000241041.7(PEX16):c.953-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,612,798 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (19 hom.)
• Consequence: PEX16 ENST00000241041.7 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.1877
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.97

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 11-45910189-A-G is Benign according to our data. Variant chr11-45910189-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 304785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-45910189-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00739 (1126/152310) while in subpopulation AFR AF= 0.0233 (968/41570). AF 95% confidence interval is 0.0221. There are 13 homozygotes in gnomad4. There are 531 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX16	NM_004813.4	c.*65T>C		3_prime_UTR_variant	11/11	ENST00000378750.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX16	ENST00000378750.10	c.*65T>C		3_prime_UTR_variant	11/11	1	NM_004813.4	P1
PEX16	ENST00000241041.7	c.953-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1
PEX16	ENST00000523721.2	n.306T>C		non_coding_transcript_exon_variant	3/3	5
PEX16	ENST00000532681.5			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00737 AC: 1122 AN: 152192 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00278 AC: 697 AN: 250450 Hom.: 10 AF XY: 0.00205 AC XY: 278 AN XY: 135652

Gnomad AFR exome AF: 0.0218

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000858

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00155 AC: 2266 AN: 1460488 Hom.: 19 Cov.: 32 AF XY: 0.00146 AC XY: 1060 AN XY: 726574

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.00373

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000725

Gnomad4 OTH exome AF: 0.00428

GnomAD4 genome AF: 0.00739 AC: 1126 AN: 152310 Hom.: 13 Cov.: 33 AF XY: 0.00713 AC XY: 531 AN XY: 74486

Gnomad4 AFR AF: 0.0233

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.00868

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peroxisome biogenesis disorder 8A (Zellweger);C3553960:Peroxisome biogenesis disorder 8B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 01, 2021

- -

Peroxisome biogenesis disorder 8A (Zellweger) Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.19
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs16938413; hg19: chr11-45931740;