6-42960723-C-G

Variant names:

• chr6-42960723-C-G
• rs10948059
• ENST00000858685.1:c.-45C>G

Variant summary

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

The NM_001318857.2(CNPY3-GNMT):​c.152-2039C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000763 in 1,310,362 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: CNPY3-GNMT NM_001318857.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.329
• Publications: 45 publications found

Genes affected

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]

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]

PEX6 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CNPY3-GNMT (HGNC:):

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=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318857.2. 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
	CNPY3-GNMT	NM_001318857.2		c.152-2039C>G		intron	N/A	NP_001305786.1
	CNPY3-GNMT	NM_001318856.2		c.9-1489C>G		intron	N/A	NP_001305785.1
	CNPY3-GNMT	NM_001318858.2		c.152-2039C>G		intron	N/A	NP_001305787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	ENST00000858685.1		c.-45C>G		5_prime_UTR	Exon 1 of 6	ENSP00000528744.1
	GNMT	ENST00000858684.1		c.-45C>G		5_prime_UTR	Exon 1 of 6	ENSP00000528743.1
	PEX6	ENST00000970120.1		c.*1761G>C		3_prime_UTR	Exon 18 of 18	ENSP00000640179.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.63e-7 AC: 1 AN: 1310362 Hom.: 0 Cov.: 27 AF XY: 0.00000157 AC XY: 1 AN XY: 637264

African (AFR) AF: 0.00 AC: 0 AN: 28836

American (AMR) AF: 0.00 AC: 0 AN: 29436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20734

East Asian (EAS) AF: 0.00 AC: 0 AN: 34000

South Asian (SAS) AF: 0.00 AC: 0 AN: 67932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4386

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1033910

Other (OTH) AF: 0.0000183 AC: 1 AN: 54568

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 8007

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.2
DANN	Benign	0.38
PhyloP100		-0.33
PromoterAI		-0.076	Neutral

Splicing

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

Other links and lift over

dbSNP: rs10948059; hg19: chr6-42928461;