6-42963928-A-C

Variant names:

• chr6-42963928-A-C
• rs886061409
• NM_000287.4:c.*407T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000287.4(PEX6):​c.*407T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (0 hom., cov: 12)
  • Exomes 𝑓: 0.00040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PEX6 NM_000287.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.00200
• Publications: 1 publications found

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

GNMT (HGNC:4415): (glycine N-methyltransferase) The protein encoded by this gene is an enzyme that catalyzes the conversion of S-adenosyl-L-methionine (along with glycine) to S-adenosyl-L-homocysteine and sarcosine. This protein is found in the cytoplasm and acts as a homotetramer. Defects in this gene are a cause of GNMT deficiency (hypermethioninemia). Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between the upstream CNPY3 (canopy FGF signaling regulator 3) gene and this gene and is represented with GeneID:107080644. [provided by RefSeq, Jan 2016]

GNMT Gene-Disease associations (from GenCC):

• glycine N-methyltransferase deficiency

  Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

CNPY3-GNMT (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000287.4. 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
	PEX6	NM_000287.4	MANE Select	c.*407T>G		3_prime_UTR	Exon 17 of 17	NP_000278.3
	PEX6	NM_001316313.2		c.*407T>G		3_prime_UTR	Exon 17 of 17	NP_001303242.1	Q13608-3
	PEX6	NR_133009.2		n.3134T>G		non_coding_transcript_exon	Exon 15 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX6	ENST00000304611.13	TSL:1 MANE Select	c.*407T>G		3_prime_UTR	Exon 17 of 17	ENSP00000303511.8	Q13608-1
	PEX6	ENST00000858654.1		c.*407T>G		3_prime_UTR	Exon 16 of 16	ENSP00000528713.1
	PEX6	ENST00000858653.1		c.*407T>G		3_prime_UTR	Exon 16 of 16	ENSP00000528712.1

Frequencies

GnomAD3 genomes AF: 0.350 AC: 23159 AN: 66232 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.342

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000396 AC: 116 AN: 292646 Hom.: 0 Cov.: 3 AF XY: 0.000361 AC XY: 57 AN XY: 157796

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

African (AFR) AF: 0.000108 AC: 1 AN: 9224

American (AMR) AF: 0.000516 AC: 11 AN: 21312

Ashkenazi Jewish (ASJ) AF: 0.000225 AC: 2 AN: 8878

East Asian (EAS) AF: 0.000452 AC: 7 AN: 15484

South Asian (SAS) AF: 0.000338 AC: 15 AN: 44376

European-Finnish (FIN) AF: 0.000280 AC: 4 AN: 14288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1170

European-Non Finnish (NFE) AF: 0.000431 AC: 70 AN: 162500

Other (OTH) AF: 0.000389 AC: 6 AN: 15414

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.349 AC: 23157 AN: 66266 Hom.: 0 Cov.: 12 AF XY: 0.330 AC XY: 10335 AN XY: 31348

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

African (AFR) AF: 0.346 AC: 6237 AN: 18052

American (AMR) AF: 0.253 AC: 1535 AN: 6066

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 647 AN: 1662

East Asian (EAS) AF: 0.336 AC: 658 AN: 1956

South Asian (SAS) AF: 0.358 AC: 634 AN: 1772

European-Finnish (FIN) AF: 0.178 AC: 588 AN: 3300

Middle Eastern (MID) AF: 0.167 AC: 14 AN: 84

European-Non Finnish (NFE) AF: 0.386 AC: 12340 AN: 32006

Other (OTH) AF: 0.339 AC: 319 AN: 942

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.158 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Peroxisome biogenesis disorder 4A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.48
PhyloP100		-0.0020
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs886061409; hg19: chr6-42931666;