1:11796321-G>A

Position:

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 same amino acid change has been previously reported as Likely benignin 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

Clinical Significance

drug response reviewed by expert panel P:3U:6B: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]

MTHFR links:

Genome browser will be placed here

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/exons	MANE	UniProt
MTHFR	NM_005957.5 linkuse as main transcript	c.665C>T	p.Ala222Val	missense_variant	5/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9 linkuse as main transcript	c.665C>T	p.Ala222Val	missense_variant	5/12	1	NM_005957.5	A1	P42898-1

Frequencies

GnomAD3 genomes

AF:

0.275

AC:

41856

AN:

151970

Hom.:

6918

Cov.:

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.:

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.:

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:6Benign:9Other:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Pathogenic:2Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	research	Neurology Department, Peking University First Hospital	Apr 23, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 17, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 16, 2019	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

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

not provided

Uncertain:2Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2017	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MTHFR: PM3, PM2:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	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. -

MTHFR THERMOLABILE POLYMORPHISM

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	clinical testing	FirmaLab, FirmaLab	-	- -
Benign, no assertion criteria provided	literature only	OMIM	Sep 29, 2023	- -

Neural tube defects, folate-sensitive

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	reference population	iDNA Genomics	-	- -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jan 06, 2022

ACMG categories: PS3,PS4,PM1,BA1 -

Gastrointestinal stromal tumor

Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

- -

Thrombophilia due to thrombin defect

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Dec 30, 2017

- -

methotrexate response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

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

Neoplasm of stomach

Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.;.;D;.;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

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

MutationAssessor

Pathogenic

3.0

M;.;.;M;.;.;.

MutationTaster

Benign

8.6e-8

P;P;P;P

PrimateAI

Uncertain

0.62

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over