chr6-42960916-T-C

Variant names:

• chr6-42960916-T-C
• rs121907888
• NM_018960.6:c.149T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_018960.6(GNMT):​c.149T>C​(p.Leu50Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,411,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: GNMT NM_018960.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.47
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 6-42960916-T-C is Pathogenic according to our data. Variant chr6-42960916-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4169.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018960.6. 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
	GNMT	NM_018960.6	MANE Select	c.149T>C	p.Leu50Pro	missense	Exon 1 of 6	NP_061833.1	Q14749
	GNMT	NM_001318865.2		c.149T>C	p.Leu50Pro	missense	Exon 1 of 6	NP_001305794.1	A0A0S2Z5F2
	CNPY3-GNMT	NM_001318857.2		c.152-1846T>C		intron	N/A	NP_001305786.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	ENST00000372808.4	TSL:1 MANE Select	c.149T>C	p.Leu50Pro	missense	Exon 1 of 6	ENSP00000361894.3	Q14749
	GNMT	ENST00000858688.1		c.149T>C	p.Leu50Pro	missense	Exon 1 of 6	ENSP00000528747.1
	GNMT	ENST00000858686.1		c.149T>C	p.Leu50Pro	missense	Exon 1 of 6	ENSP00000528745.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000183 AC: 3 AN: 164362 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000232

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1411522 Hom.: 0 Cov.: 33 AF XY: 0.00000429 AC XY: 3 AN XY: 698530

African (AFR) AF: 0.00 AC: 0 AN: 32538

American (AMR) AF: 0.00 AC: 0 AN: 37980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25348

East Asian (EAS) AF: 0.000107 AC: 4 AN: 37340

South Asian (SAS) AF: 0.00 AC: 0 AN: 80774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5394

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091006

Other (OTH) AF: 0.0000170 AC: 1 AN: 58670

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000174 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Glycine N-methyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.89		Loss of stability (P = 0.0631)
MVP		0.92
MPC		2.6
ClinPred		0.85	D
GERP RS		4.8
PromoterAI		0.027	Neutral
Varity_R		0.91
gMVP		0.96
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs121907888; hg19: chr6-42928654;