NM_000254.3:c.3380dupA

Variant names:

• chr1-236894530-C-CA
• rs797044445
• NM_000254.3:c.3380dupA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000254.3(MTR):​c.3380dupA​(p.Ala1128GlyfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTR NM_000254.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.69
• Publications: 0 publications found

Genes affected

MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

MTR Gene-Disease associations (from GenCC):

• methylcobalamin deficiency type cblG

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-236894530-C-CA is Pathogenic according to our data. Variant chr1-236894530-C-CA is described in ClinVar as Pathogenic. ClinVar VariationId is 14284.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. 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
	MTR	NM_000254.3	MANE Select	c.3380dupA	p.Ala1128GlyfsTer16	frameshift	Exon 30 of 33	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.3227dupA	p.Ala1077GlyfsTer16	frameshift	Exon 29 of 32	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.3191dupA	p.Ala1065GlyfsTer16	frameshift	Exon 28 of 31	NP_001397871.1	A0A7P0TAJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.3380dupA	p.Ala1128GlyfsTer16	frameshift	Exon 30 of 33	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.3227dupA	p.Ala1077GlyfsTer16	frameshift	Exon 29 of 32	ENSP00000441845.1	Q99707-2
	MTR	ENST00000366576.3	TSL:1	c.2042dupA	p.Ala682GlyfsTer16	frameshift	Exon 17 of 20	ENSP00000355535.3	B1ANE3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Methylcobalamin deficiency type cblG (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=2/198	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: rs797044445; hg19: chr1-237057830;