chr1-11796321-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1PP3BP4_StrongBA1

The NM_005957.5(MTHFR):​c.665C>T​(p.Ala222Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,613,846 control chromosomes in the GnomAD database, including 87,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A222A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.28 ( 6918 hom., cov: 32)
Exomes 𝑓: 0.32 ( 80805 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

8
6
4

Clinical Significance

drug response reviewed by expert panel P:3U:5B:9O:3

Conservation

PhyloP100: 9.14
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_005957.5
PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.0016527474).
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MTHFRNM_005957.5 linkc.665C>T p.Ala222Val missense_variant Exon 5 of 12 ENST00000376590.9 NP_005948.3 P42898-1Q8IU67Q59GJ6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MTHFRENST00000376590.9 linkc.665C>T p.Ala222Val missense_variant Exon 5 of 12 1 NM_005957.5 ENSP00000365775.3 P42898-1

Frequencies

GnomAD3 genomes
AF:
0.275
AC:
41856
AN:
151970
Hom.:
6918
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.112
Gnomad AMI
AF:
0.484
Gnomad AMR
AF:
0.444
Gnomad ASJ
AF:
0.461
Gnomad EAS
AF:
0.302
Gnomad SAS
AF:
0.147
Gnomad FIN
AF:
0.235
Gnomad MID
AF:
0.297
Gnomad NFE
AF:
0.337
Gnomad OTH
AF:
0.300
GnomAD3 exomes
AF:
0.315
AC:
79177
AN:
251468
Hom.:
14637
AF XY:
0.309
AC XY:
41934
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.108
Gnomad AMR exome
AF:
0.503
Gnomad ASJ exome
AF:
0.457
Gnomad EAS exome
AF:
0.290
Gnomad SAS exome
AF:
0.145
Gnomad FIN exome
AF:
0.231
Gnomad NFE exome
AF:
0.340
Gnomad OTH exome
AF:
0.330
GnomAD4 exome
AF:
0.323
AC:
471698
AN:
1461758
Hom.:
80805
Cov.:
40
AF XY:
0.318
AC XY:
231451
AN XY:
727162
show subpopulations
Gnomad4 AFR exome
AF:
0.106
Gnomad4 AMR exome
AF:
0.489
Gnomad4 ASJ exome
AF:
0.460
Gnomad4 EAS exome
AF:
0.355
Gnomad4 SAS exome
AF:
0.149
Gnomad4 FIN exome
AF:
0.233
Gnomad4 NFE exome
AF:
0.337
Gnomad4 OTH exome
AF:
0.308
GnomAD4 genome
AF:
0.275
AC:
41850
AN:
152088
Hom.:
6918
Cov.:
32
AF XY:
0.273
AC XY:
20316
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.112
Gnomad4 AMR
AF:
0.444
Gnomad4 ASJ
AF:
0.461
Gnomad4 EAS
AF:
0.302
Gnomad4 SAS
AF:
0.148
Gnomad4 FIN
AF:
0.235
Gnomad4 NFE
AF:
0.337
Gnomad4 OTH
AF:
0.298
Alfa
AF:
0.337
Hom.:
23149
Bravo
AF:
0.291
TwinsUK
AF:
0.330
AC:
1224
ALSPAC
AF:
0.334
AC:
1288
ESP6500AA
AF:
0.122
AC:
536
ESP6500EA
AF:
0.347
AC:
2983
ExAC
AF:
0.304
AC:
36865
Asia WGS
AF:
0.190
AC:
662
AN:
3478

ClinVar

Significance: drug response
Submissions summary: Pathogenic:3Uncertain:5Benign:9Other:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:2Uncertain:1Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 23, 2020
Neurology Department, Peking University First Hospital
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Jan 17, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: No criteria apply. This variant was detected in homozygous state. -

Dec 07, 2019
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 16, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_005957.4(MTHFR):c.665C>T(A222V) is a common variant present in approximately 30% of the general population. While many individuals who are homozygous for this variant are asymptomatic, some may have mild MTHFR deficiency associated with increased plasma homocysteine. Sources cited for classification include the following: PMID 7647779, 8837319, 9545406, 11781870, 12560871, 8903338, 9789068, 11929966, 15565101, 17436239, 12356947, 9133512, 12196644 and 9798595. Classification of NM_005957.4(MTHFR):c.665C>T(A222V) is based on the following criteria: This is a well-established variant in the literature that has been observed more frequently in patients with mild MTHFR deficiency than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening. -

not specified Benign:4
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 25, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Uncertain:1Other:2
Jan 13, 2017
Eurofins Ntd Llc (ga)
Significance: other
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Nov 22, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: association
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MTHFR c.665C>T; p.Ala222Val variant (rs1801133), also known as C677T or the thermolabile variant, is listed in the ClinVar database (Variation ID: 3520) and is observed in the general population with an overall allele frequency of 30.8% (87,234/282,784 alleles including 15,819 homozygotes) in the Genome Aggregation Database. The thermolabile c.665C>T variant in the homozygous state has been correlated with reduced enzyme activity and increased homocysteine (Frosst 1995). The practice guidelines from The American College of Medical Genetics state that this variant in the heterozygous state is unlikely to be of clinical significance (Hickey 2013); however, a possible effect of this variant when paired with a pathogenic MTHFR variant on the opposite chromosome cannot be excluded. Additionally, the practice guidelines state that an individual who is homozygous for the c.665C>T; p.Ala222Val variant and has elevated homocysteine may be at mildly increased risk for venous thromboembolism and recurrent pregnancy loss (Hickey 2013). The variant is considered a ''susceptibility'' or an ''association'' variant. REFERENCES Frosst P et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May;10(1):111-3. PMID: 7647779. Hickey SE et al. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153-6. PMID: 23288205. -

Jan 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MTHFR: PM3, PM2:Supporting -

MTHFR THERMOLABILE POLYMORPHISM Pathogenic:1Benign:1
Sep 29, 2023
OMIM
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
FirmaLab, FirmaLab
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Neural tube defects, folate-sensitive Benign:2
May 28, 2019
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
iDNA Genomics
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: reference population

- -

See cases Uncertain:1
Jan 06, 2022
Institute of Human Genetics, University Hospital Muenster
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG categories: PS3,PS4,PM1,BA1 -

Gastrointestinal stromal tumor Uncertain:1
-
Department of Pharmacy and Biotechnology, University of Bologna
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: case-control

- -

Thrombophilia due to thrombin defect Uncertain:1
Dec 30, 2017
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: curation

- -

methotrexate response - Toxicity Other:1
Mar 24, 2021
PharmGKB
Significance: drug response
Review Status: reviewed by expert panel
Collection Method: curation

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Toxicity

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D;.;.;D;.;.;.
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.83
.;T;.;T;T;T;D
MetaRNN
Benign
0.0017
T;T;T;T;T;T;T
MetaSVM
Benign
-1.5
T
MutationAssessor
Pathogenic
3.0
M;.;.;M;.;.;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.8
D;D;D;D;.;.;.
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0020
D;D;D;D;.;.;.
Sift4G
Uncertain
0.053
T;D;D;T;.;.;.
Polyphen
1.0
D;.;.;D;.;.;.
Vest4
0.47
MPC
0.93
ClinPred
0.020
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.94

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1801133; hg19: chr1-11856378; COSMIC: COSV64876755; COSMIC: COSV64876755; API