6-42963928-A-T

Variant names:

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

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>A 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000068 (0 hom., cov: 12)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: PEX6 NM_000287.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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=-0.89).

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>A		3_prime_UTR	Exon 17 of 17	NP_000278.3
	PEX6	NM_001316313.2		c.*407T>A		3_prime_UTR	Exon 17 of 17	NP_001303242.1	Q13608-3
	PEX6	NR_133009.2		n.3134T>A		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>A		3_prime_UTR	Exon 17 of 17	ENSP00000303511.8	Q13608-1
	PEX6	ENST00000858654.1		c.*407T>A		3_prime_UTR	Exon 16 of 16	ENSP00000528713.1
	PEX6	ENST00000858653.1		c.*407T>A		3_prime_UTR	Exon 16 of 16	ENSP00000528712.1

Frequencies

GnomAD3 genomes AF: 0.0000678 AC: 5 AN: 73774 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000146

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: 0.0000560

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000332 AC: 1 AN: 301408 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 162552

African (AFR) AF: 0.00 AC: 0 AN: 9344

American (AMR) AF: 0.00 AC: 0 AN: 21932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9052

East Asian (EAS) AF: 0.00 AC: 0 AN: 15898

South Asian (SAS) AF: 0.00 AC: 0 AN: 46146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14718

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1192

European-Non Finnish (NFE) AF: 0.00000598 AC: 1 AN: 167282

Other (OTH) AF: 0.00 AC: 0 AN: 15844

GnomAD4 genome AF: 0.0000678 AC: 5 AN: 73774 Hom.: 0 Cov.: 12 AF XY: 0.0000575 AC XY: 2 AN XY: 34754

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

African (AFR) AF: 0.000101 AC: 2 AN: 19886

American (AMR) AF: 0.000146 AC: 1 AN: 6866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1844

East Asian (EAS) AF: 0.00 AC: 0 AN: 2190

South Asian (SAS) AF: 0.00 AC: 0 AN: 1944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 126

European-Non Finnish (NFE) AF: 0.0000560 AC: 2 AN: 35694

Other (OTH) AF: 0.00 AC: 0 AN: 1048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0171690), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.48
PhyloP100		-0.0020
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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;