rs140695185

Variant names:

• chr11-45914684-T-C
• rs140695185
• NM_004813.4:c.461A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-45914684-T-C
• chr11-45914684-T-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_004813.4(PEX16):​c.461A>G​(p.Asp154Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D154D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: PEX16 NM_004813.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002515
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.887
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028835416).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000249 (38/152320) while in subpopulation AFR AF = 0.000722 (30/41564). AF 95% confidence interval is 0.000519. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004813.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX16	NM_004813.4	MANE Select	c.461A>G	p.Asp154Gly	missense splice_region	Exon 6 of 11	NP_004804.2
	PEX16	NM_057174.3		c.461A>G	p.Asp154Gly	missense splice_region	Exon 6 of 11	NP_476515.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX16	ENST00000378750.10	TSL:1 MANE Select	c.461A>G	p.Asp154Gly	missense splice_region	Exon 6 of 11	ENSP00000368024.5
	PEX16	ENST00000241041.7	TSL:1	c.461A>G	p.Asp154Gly	missense splice_region	Exon 6 of 11	ENSP00000241041.3
	PEX16	ENST00000532681.5	TSL:3	c.176A>G	p.Asp59Gly	missense splice_region	Exon 6 of 11	ENSP00000434654.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251370 AF XY: 0.0000515

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461462 Hom.: 0 Cov.: 33 AF XY: 0.0000468 AC XY: 34 AN XY: 727052

African (AFR) AF: 0.00111 AC: 37 AN: 33466

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111734

Other (OTH) AF: 0.000132 AC: 8 AN: 60386

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74482

African (AFR) AF: 0.000722 AC: 30 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000573 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Peroxisome biogenesis disorder (1)
-	1	-	Peroxisome biogenesis disorder 8A (Zellweger) (1)
-	1	-	Peroxisome biogenesis disorder 8A (Zellweger);C3553960:Peroxisome biogenesis disorder 8B (1)
-	1	-	PEX16-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.89
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.016
Sift	Benign	0.090	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.15
MVP		0.33
MPC		0.46
ClinPred		0.022	T
GERP RS		2.4
Varity_R		0.15
gMVP		0.41
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs140695185; hg19: chr11-45936235;