NM_000254.3:c.1_2delAT
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000254.3(MTR):c.1_2delAT(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MTR
NM_000254.3 frameshift, start_lost
NM_000254.3 frameshift, start_lost
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.278
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 cblGInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 72 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-236795703-CAT-C is Pathogenic according to our data. Variant chr1-236795703-CAT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 452311.Status of the report is criteria_provided_single_submitter, 1 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 | MANE Select | c.1_2delAT | p.Met1fs | frameshift start_lost | Exon 1 of 33 | NP_000245.2 | Q99707-1 | ||
| MTR | c.1_2delAT | p.Met1fs | frameshift start_lost | Exon 1 of 32 | NP_001278868.1 | Q99707-2 | |||
| MTR | c.1_2delAT | p.Met1fs | frameshift start_lost | Exon 1 of 31 | NP_001397871.1 | A0A7P0TAJ0 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MTR | TSL:1 MANE Select | c.1_2delAT | p.Met1fs | frameshift start_lost | Exon 1 of 33 | ENSP00000355536.5 | Q99707-1 | ||
| MTR | TSL:1 | c.1_2delAT | p.Met1fs | frameshift start_lost | Exon 1 of 32 | ENSP00000441845.1 | Q99707-2 | ||
| MTR | c.1_2delAT | p.Met1fs | frameshift start_lost | Exon 1 of 32 | ENSP00000505600.1 | A0A7P0T9G7 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152262Hom.: 0 Cov.: 33 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152262
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
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Gnomad SAS
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461778Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727194 show subpopulations
GnomAD4 exome
AF:
AC:
3
AN:
1461778
Hom.:
AF XY:
AC XY:
1
AN XY:
727194
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53320
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
2
AN:
1112000
Other (OTH)
AF:
AC:
1
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.458
Heterozygous variant carriers
0
1
1
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2
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome 0.00000657 AC: 1AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74394 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152262
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74394
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41476
American (AMR)
AF:
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5196
South Asian (SAS)
AF:
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68040
Other (OTH)
AF:
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Likely pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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