chr1-11796321-G-A

Variant names:

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

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Likely benign

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received -1 ACMG points: 3P and 4B. O4_SupportingO6_SupportingO7_SupportingB1_Strong

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) The variant has been observed in cBioPortal in 7 samples across 6 studies and 6 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). 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: 8626 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: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen, G2P

Classification according to ACGS-UK Somatic Oncogenicity v2025

Our verdict: Likely_benign. The variant received -1 ACMG points.

• O4: Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=7 | studies=6 | cancer types=6 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
• O6: Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
• O7: Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 3 pathogenic, 1 benign (OR vs. background: 11.7); Variant does not impact splicing — splice-hotspot path not applicable
• B1: GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.484 — exceeds 1% threshold (B1 applied)

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.665C>T	p.Ala222Val	missense	Exon 5 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.788C>T	p.Ala263Val	missense	Exon 5 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.785C>T	p.Ala262Val	missense	Exon 5 of 12	NP_001397679.1	Q5SNW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.665C>T	p.Ala222Val	missense	Exon 5 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.785C>T	p.Ala262Val	missense	Exon 5 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.665C>T	p.Ala222Val	missense	Exon 5 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41856 AN: 151970 Hom.: 6918 Cov.: 32

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

GnomAD2 exomes AF: 0.315 AC: 79177 AN: 251468 AF XY: 0.309

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 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

African (AFR) AF: 0.106 AC: 3560 AN: 33476

American (AMR) AF: 0.489 AC: 21885 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 12021 AN: 26134

East Asian (EAS) AF: 0.355 AC: 14074 AN: 39698

South Asian (SAS) AF: 0.149 AC: 12847 AN: 86258

European-Finnish (FIN) AF: 0.233 AC: 12425 AN: 53398

Middle Eastern (MID) AF: 0.260 AC: 1499 AN: 5768

European-Non Finnish (NFE) AF: 0.337 AC: 374815 AN: 1111916

Other (OTH) AF: 0.308 AC: 18572 AN: 60386

GnomAD4 genome AF: 0.275 AC: 41850 AN: 152088 Hom.: 6918 Cov.: 32 AF XY: 0.273 AC XY: 20316 AN XY: 74360

African (AFR) AF: 0.112 AC: 4641 AN: 41510

American (AMR) AF: 0.444 AC: 6772 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1598 AN: 3470

East Asian (EAS) AF: 0.302 AC: 1561 AN: 5174

South Asian (SAS) AF: 0.148 AC: 713 AN: 4828

European-Finnish (FIN) AF: 0.235 AC: 2494 AN: 10592

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22918 AN: 67942

Other (OTH) AF: 0.298 AC: 628 AN: 2108

Alfa AF: 0.324 Hom.: 41832

Bravo AF: 0.291

Asia WGS AF: 0.190 AC: 662 AN: 3478

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.392 AC: 48018 AN: 122651

Turkish Variome AF: 0.299 AC: 2008 AN: 6714 Hom.: 304

WBBC (Westlake BioBank for Chinese) pilot AF: 0.349 AC: 3123 AN: 8960 Hom.: 570

ABraOM SABE-WGS-1171 AF: 0.335 AC: 785 AN: 2342 Hom.: 114

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

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.5	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.053	T
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.94
Mutation Taster		=36/64	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs1801133;

hg19: chr1-11856378;

COSMIC: COSV64876755;

COSMIC: COSV64876755;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar