NM_005957.5:c.643_645delAAG
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_005957.5(MTHFR):c.643_645delAAG(p.Lys215del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
MTHFR
NM_005957.5 conservative_inframe_deletion
NM_005957.5 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.30
Publications
1 publications found
Genes affected
MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]
MTHFR Gene-Disease associations (from GenCC):
- homocystinuria due to methylene tetrahydrofolate reductase deficiencyInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_005957.5. Strenght limited to Supporting due to length of the change: 1aa.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_005957.5. 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 |
|---|---|---|---|---|---|---|---|---|---|
| MTHFR | NM_005957.5 | MANE Select | c.643_645delAAG | p.Lys215del | conservative_inframe_deletion | Exon 5 of 12 | NP_005948.3 | ||
| MTHFR | NM_001330358.2 | c.766_768delAAG | p.Lys256del | conservative_inframe_deletion | Exon 5 of 12 | NP_001317287.1 | |||
| MTHFR | NM_001410750.1 | c.763_765delAAG | p.Lys255del | conservative_inframe_deletion | Exon 5 of 12 | NP_001397679.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MTHFR | ENST00000376590.9 | TSL:1 MANE Select | c.643_645delAAG | p.Lys215del | conservative_inframe_deletion | Exon 5 of 12 | ENSP00000365775.3 | ||
| MTHFR | ENST00000423400.7 | TSL:1 | c.763_765delAAG | p.Lys255del | conservative_inframe_deletion | Exon 5 of 12 | ENSP00000398908.3 | ||
| MTHFR | ENST00000376592.6 | TSL:1 | c.643_645delAAG | p.Lys215del | conservative_inframe_deletion | Exon 5 of 12 | ENSP00000365777.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152208
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
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GnomAD2 exomes AF: 0.00000795 AC: 2AN: 251490 AF XY: 0.00000736 show subpopulations
GnomAD2 exomes
AF:
AC:
2
AN:
251490
AF XY:
Gnomad AFR exome
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Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461040Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 726852 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461040
Hom.:
AF XY:
AC XY:
1
AN XY:
726852
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33472
American (AMR)
AF:
AC:
0
AN:
44652
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26114
East Asian (EAS)
AF:
AC:
0
AN:
39694
South Asian (SAS)
AF:
AC:
0
AN:
86218
European-Finnish (FIN)
AF:
AC:
0
AN:
53394
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111360
Other (OTH)
AF:
AC:
0
AN:
60370
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
GnomAD4 genome 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152208
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74362
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41452
American (AMR)
AF:
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5198
South Asian (SAS)
AF:
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68030
Other (OTH)
AF:
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
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 as Germline
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
1
-
Homocystinuria due to methylene tetrahydrofolate reductase deficiency (2)
-
1
-
not specified (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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