1-11796321-G-T

Variant names:

• chr1-11796321-G-T
• rs1801133
• NM_005957.5:c.665C>A
• MTHFR p.Ala222Asp

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PP3_Moderate

The NM_005957.5(MTHFR):c.665C>A (p.Ala222Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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); p.A222V: drug_response (ClinVar VariationId 3520, 3 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.14
• Publications: 1 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_pathogenic. The variant received 6 points.

• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 3 pathogenic, 1 benign (OR vs. background: 11.7).
• PM2: Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

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>A	p.Ala222Asp	missense	Exon 5 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.788C>A	p.Ala263Asp	missense	Exon 5 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.785C>A	p.Ala262Asp	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>A	p.Ala222Asp	missense	Exon 5 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.785C>A	p.Ala262Asp	missense	Exon 5 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.665C>A	p.Ala222Asp	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 3 sources Large-scale international reference populations
GnomAD3 genomes					32
GnomAD4 exome					40
GnomAD4 genome					32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	30
AlphaMissense	Pathogenic	-	0.98
BayesDel_addAF	Pathogenic	D	0.58
BayesDel_noAF	Pathogenic	-	0.59
CADD	Pathogenic	-	29
DANN	Uncertain	-	1.0
DEOGEN2	Pathogenic	D	0.98
Eigen	Pathogenic	-	0.94
Eigen_PC	Pathogenic	-	0.79
FATHMM_MKL	Pathogenic	D	0.98
FuncVEP CTI	Pathogenic	-	0.94
GPN-Star LLR	N/A	-	-8.8
GPN-Star score	N/A	-	8.8
LIST_S2	Uncertain	D	0.96
M_CAP	Pathogenic	D	0.44
MetaRNN	Pathogenic	D	0.94
MetaSVM	Pathogenic	D	1.1
Mutation Taster	N/A	disease causing	14/86
MutationAssessor	Pathogenic	H	4.9
PhyloP100	Pathogenic	-	9.1
popEVE	Benign	-	-4.3
PrimateAI	Uncertain	T	0.69
PromoterAI	N/A	Neutral	0.034
PROVEAN	Pathogenic	D	-5.0
RBP_binding_hub_radar	N/A	-	0.0
RBP_regulation_power_radar	N/A	-	1.7
REVEL	Pathogenic	-	0.92
Sift	Uncertain	D	0.0010
Sift4G	Uncertain	D	0.0030
Varity_R	N/A	-	0.99
VESM-3B	Benign	-	-15

Showing 31 of 31 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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar