1-11796321-G-A

Variant names:

• chr1-11796321-G-A
• rs1801133
• NM_005957.5:c.665C>T
• MTHFR p.Ala222Val

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). BA1PS3PP3_Moderate

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 cumulative frequency of 0.318 (AC=513,548) in the gnomAD database across 1,613,846 control chromosomes, including 87,723 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.484. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.14). Variant has been reported in ClinVar as Uncertain Significance (★★★). ClinVar reports functional evidence for this variant: "SCV001194043: 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. PMID 7647779, 8837319, 9545406, 11781870, 12560871, 8903338, 9789068, 11929966, 15565101, 17436239, 12356947, 9133512, 12196644 and 9798595.". Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.A222= (synonymous): Likely_benign (ClinVar VariationId 1658853, 1 star); p.A222V: Likely_benign (ClinVar VariationId 2194685, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.28 (6918 hom., cov: 32)
  • Exomes 𝑓: 0.32 (80805 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: drug response reviewed by expert panel P:5 U:6 B:9 O:3
• Conservation: PhyloP100: 9.14
• Publications: 8966 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 deficiency

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV001194043: 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. PMID 7647779, 8837319, 9545406, 11781870, 12560871, 8903338, 9789068, 11929966, 15565101, 17436239, 12356947, 9133512, 12196644 and 9798595.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4839 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MTHFR NM_005957.5	MANE Select	c.665C>T p.Ala222Val	missense	Exon 5 of 12	Prot: NP_005948.3
	MTHFR NM_001330358.2		c.788C>T p.Ala263Val	missense	Exon 5 of 12	Prot: NP_001317287.1 UniProt:
	MTHFR NM_001410750.1		c.785C>T p.Ala262Val	missense	Exon 5 of 12	Prot: NP_001397679.1 UniProt:

MTHFR NM_005957.5

MANE Select

HGVSc / HGVSpc.665C>Tp.Ala222Val

Exon rankExon 5 of 12

missense

Prot: NP_005948.3

MTHFR NM_001330358.2

HGVSc / HGVSpc.788C>Tp.Ala263Val

Exon rankExon 5 of 12

missense

Prot: NP_001317287.1UniProt: P42898-2

MTHFR NM_001410750.1

HGVSc / HGVSpc.785C>Tp.Ala262Val

Exon rankExon 5 of 12

missense

Prot: NP_001397679.1UniProt: Q5SNW7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MTHFR ENST00000376590.9	TSL:1MANE Select	c.665C>T p.Ala222Val	missense	Exon 5 of 12	Prot: ENSP00000365775.3 UniProt:
	MTHFR ENST00000423400.7	TSL:1	c.785C>T p.Ala262Val	missense	Exon 5 of 12	Prot: ENSP00000398908.3 UniProt:
	MTHFR ENST00000376592.6	TSL:1	c.665C>T p.Ala222Val	missense	Exon 5 of 12	Prot: ENSP00000365777.1 UniProt:

MTHFR ENST00000376590.9

TSL:1MANE Select

HGVSc / HGVSpc.665C>Tp.Ala222Val

Exon rankExon 5 of 12

missense

Prot: ENSP00000365775.3UniProt: P42898-1

MTHFR ENST00000423400.7

TSL:1

HGVSc / HGVSpc.785C>Tp.Ala262Val

Exon rankExon 5 of 12

missense

Prot: ENSP00000398908.3UniProt: Q5SNW7

MTHFR ENST00000376592.6

TSL:1

HGVSc / HGVSpc.665C>Tp.Ala222Val

Exon rankExon 5 of 12

missense

Prot: ENSP00000365777.1UniProt: P42898-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.275	AC:41856	Hom:6918	AN:151970	Cov:32
GnomAD2 exomes	AF: 0.315	AC:79177	Hom:	AN:251468	Cov:
GnomAD4 exome	AF: 0.323	AC:471698	Hom:80805	AN:1461758	Cov:40
GnomAD4 genome	AF: 0.275	AC:41850	Hom:6918	AN:152088	Cov:32
TOPMed (Bravo)	AF: 0.291	AC:77089	Hom:13642	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.322	AC:256394	Hom:44120	AN:796766	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.335	AC:785	Hom:114	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.400	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.323	AC:97	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.271	AC:3519	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.190	AC:662	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.427	AC:3089	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.129	AC:260	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.392	AC:48018	Hom:9439	AN:122651	Cov:
Turkish Variome	AF: 0.299	AC:2008	Hom:304	AN:6714	Cov:
UK10K	AF: 0.332	AC:2512	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.349	AC:3123	Hom:570	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.310 *	3433	11062	0.295 *	5183	17576
BipEx(Bipolar disorder (including schizoaffective))	0.327	9286	28420	0.322	9275	28842
Epi25(Epilepsy)	0.320	13426	41958	0.336	22458	66886
SCHEMA(Schizophrenia)	0.318	47202	148404	0.336	83436	248594

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	1	2	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (6)
-	-	4	not specified (4)
-	1	2	Neural tube defects, folate-sensitive (3)
1	-	1	MTHFR THERMOLABILE POLYMORPHISM (2)
-	1	-	Gastrointestinal stromal tumor (1)
-	1	-	not provided (3)
-	1	-	See cases (1)
-	1	-	Thrombophilia due to thrombin defect (1)
-	-	-	methotrexate response - Toxicity (1)
-	-	-	Stroke disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
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
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-7.0
GPN-Star score	N/A	7.0
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.5	T
Mutation Taster	N/A	36/64	polymorphism (auto)
MutationAssessor	Pathogenic	3.0	M
PhyloP100	Pathogenic	9.1
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.62	T
PromoterAI	N/A	-0.048	Neutral
PROVEAN	Uncertain	-3.8	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.053	T
Varity_R	N/A	0.83
VESM-3B	Benign	-9.8

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

4 no calibration

4 assays found for this variant.

No calibration: 4 assays (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Protein level

MTHFR at 25ug/ml folate in WT background

MTHFR DMS

• Gene: MTHFR
• Score: 0.594 · p.Ala222Val (assay numbering)

No calibration data

This score is at approximately the 37th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

MTHFR at 12ug/ml folate in WT background

MTHFR DMS

• Gene: MTHFR
• Score: 0.382 · p.Ala222Val (assay numbering)

No calibration data

This score is at approximately the 23th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

MTHFR at 200ug/ml folate in WT background

MTHFR DMS

• Gene: MTHFR
• Score: 0.782 · p.Ala222Val (assay numbering)

No calibration data

This score is at approximately the 46th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

MTHFR at 100ug/ml folate in WT background

MTHFR DMS

• Gene: MTHFR
• Score: 0.704 · p.Ala222Val (assay numbering)

No calibration data

This score is at approximately the 45th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs1801133;

hg19: chr1-11856378;

COSMIC: COSV64876755;

COSMIC: COSV64876755;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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