rs35214605

Variant names:

• chr11-45914138-C-A
• rs35214605
• NM_004813.4:c.760G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-45914138-C-A
• chr11-45914138-C-G
• chr11-45914138-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004813.4(PEX16):​c.760G>T​(p.Val254Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V254M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PEX16 NM_004813.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.702
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061854213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX16	NM_004813.4	c.760G>T	p.Val254Leu	missense_variant	Exon 8 of 11	ENST00000378750.10	NP_004804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX16	ENST00000378750.10	c.760G>T	p.Val254Leu	missense_variant	Exon 8 of 11	1	NM_004813.4	ENSP00000368024.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448588 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 719700

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33098

American (AMR) AF: 0.00 AC: 0 AN: 42816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25850

East Asian (EAS) AF: 0.00 AC: 0 AN: 38822

South Asian (SAS) AF: 0.00 AC: 0 AN: 84684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105444

Other (OTH) AF: 0.00 AC: 0 AN: 59812

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.025	.;T;.;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	D;T;D;D;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.062	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.055	N;N;.;.;.
PhyloP100		0.70
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.25	N;N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.26	T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;.
Polyphen		0.0040	B;B;.;.;.
Vest4		0.11
MutPred		0.14		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);.;.;.;
MVP		0.37
MPC		0.35
ClinPred		0.12	T
GERP RS		3.5
Varity_R		0.038
gMVP		0.24
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs35214605; hg19: chr11-45935689;