NM_004813.4:c.*376G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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
• 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 -9 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

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

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

African (AFR) AF: 0.000160 AC: 2 AN: 12510

American (AMR) AF: 0.000684 AC: 14 AN: 20464

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

East Asian (EAS) AF: 0.0172 AC: 524 AN: 30530

South Asian (SAS) AF: 0.00194 AC: 91 AN: 47012

European-Finnish (FIN) AF: 0.00529 AC: 151 AN: 28522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1936

European-Non Finnish (NFE) AF: 0.000529 AC: 140 AN: 264660

Other (OTH) AF: 0.00156 AC: 40 AN: 25566

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

African (AFR) AF: 0.000337 AC: 14 AN: 41560

American (AMR) AF: 0.000588 AC: 9 AN: 15308

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

East Asian (EAS) AF: 0.0147 AC: 76 AN: 5186

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00536 AC: 57 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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
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;