rs993758988

Variant names:

• chr6-143450857-C-T
• rs993758988
• NM_003630.3:c.-186C>T

Variant summary

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

The NM_003630.3(PEX3):​c.-186C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 762,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PEX3 NM_003630.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96
• Publications: 0 publications found

Genes affected

PEX3 (HGNC:8858): (peroxisomal biogenesis factor 3) The product of this gene is involved in peroxisome biosynthesis and integrity. It assembles membrane vesicles before the matrix proteins are translocated. Peroxins (PEXs) are proteins that are essential for the assembly of functional peroxisomes. The peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous autosomal recessive, lethal diseases characterized by multiple defects in peroxisome function. The peroxisomal biogenesis disorders are a heterogeneous group with at least 14 complementation groups and with more than 1 phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene are a cause Zellweger syndrome (ZWS). [provided by RefSeq, Oct 2008]

ADAT2 (HGNC:21172): (adenosine deaminase tRNA specific 2) Predicted to enable tRNA-specific adenosine-34 deaminase activity. Predicted to be involved in tRNA wobble adenosine to inosine editing. Predicted to be located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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 (BayesDel_noAF=-0.75).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003630.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX3	NM_003630.3	MANE Select	c.-186C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_003621.1	P56589
	PEX3	NM_003630.3	MANE Select	c.-186C>T		5_prime_UTR	Exon 1 of 12	NP_003621.1	P56589
	ADAT2	NM_182503.3	MANE Select	c.-199G>A		upstream_gene	N/A	NP_872309.2	Q7Z6V5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX3	ENST00000367591.5	TSL:1 MANE Select	c.-186C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000356563.4	P56589
	PEX3	ENST00000367591.5	TSL:1 MANE Select	c.-186C>T		5_prime_UTR	Exon 1 of 12	ENSP00000356563.4	P56589
	PEX3	ENST00000918413.1		c.-186C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000588472.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.0000213 AC: 13 AN: 610540 Hom.: 0 Cov.: 7 AF XY: 0.0000214 AC XY: 7 AN XY: 327564

African (AFR) AF: 0.000176 AC: 3 AN: 17026

American (AMR) AF: 0.00 AC: 0 AN: 36484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17810

East Asian (EAS) AF: 0.00 AC: 0 AN: 35140

South Asian (SAS) AF: 0.00 AC: 0 AN: 61984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2494

European-Non Finnish (NFE) AF: 0.0000271 AC: 10 AN: 368836

Other (OTH) AF: 0.00 AC: 0 AN: 32068

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.0000724 AC: 3 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peroxisome biogenesis disorder 10A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		2.0
PromoterAI		-0.048	Neutral

Splicing

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

Other links and lift over

dbSNP: rs993758988; hg19: chr6-143771994;