chr1-11796321-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: 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: Natera, PanelApp Australia, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

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

• PS3: 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.
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• BA1: 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	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

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

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 prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	26
AlphaMissense	Pathogenic	-	0.63
BayesDel_addAF	Uncertain	D	0.12
BayesDel_noAF	Pathogenic	-	0.55
CADD	Pathogenic	-	28
DANN	Pathogenic	-	1.0
DEOGEN2	Pathogenic	D	0.94
Eigen	Pathogenic	-	0.74
Eigen_PC	Uncertain	-	0.66
FATHMM_MKL	Pathogenic	D	0.98
GPN-Star LLR	N/A	-	-7.0
GPN-Star score	N/A	-	7.0
LIST_S2	Benign	T	0.83
MetaRNN	Benign	T	0.0017
MetaSVM	Benign	T	-1.5
Mutation Taster	N/A	polymorphism (auto)	36/64
MutationAssessor	Pathogenic	M	3.0
PhyloP100	Pathogenic	-	9.1
popEVE	Benign	-	-3.4
PrimateAI	Uncertain	T	0.62
PromoterAI	N/A	Neutral	-0.048
PROVEAN	Uncertain	D	-3.8
RBP_binding_hub_radar	N/A	-	0.0
RBP_regulation_power_radar	N/A	-	1.7
REVEL	Pathogenic	-	0.84
Sift	Uncertain	D	0.0020
Sift4G	Uncertain	T	0.053
Varity_R	N/A	-	0.83
VESM-3B	Benign	-	-9.8

Showing 29 of 29 scores

Splicing Scores

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

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.

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