1-11796321-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP3 BP4_Strong BA1

The NM_001330358.2(MTHFR):​c.788C>T​(p.Ala263Val) 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 the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A263A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (6918 hom., cov: 32)
  • Exomes 𝑓: 0.32 (80805 hom.)
• Consequence: MTHFR NM_001330358.2 missense
• Clinical Significance: drug response reviewed by expert panel P:3 U:6 B:9 O:3
• Conservation: PhyloP100: 9.14
• Publications: 8493 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), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001330358.2
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330358.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	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
	MTHFR	NM_001410750.1		c.785C>T	p.Ala262Val	missense	Exon 5 of 12	NP_001397679.1

Ensembl Transcripts

Selected	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
	MTHFR	ENST00000423400.7	TSL:1	c.785C>T	p.Ala262Val	missense	Exon 5 of 12	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.665C>T	p.Ala222Val	missense	Exon 5 of 12	ENSP00000365777.1

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

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

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	2	2	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (6)
-	-	4	not specified (4)
1	-	1	MTHFR THERMOLABILE POLYMORPHISM (2)
-	-	2	Neural tube defects, folate-sensitive (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)

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
Polyphen		1.0	D
Vest4		0.47
MPC		0.93
ClinPred		0.020	T
GERP RS		5.1
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

Other links and lift over

dbSNP: rs1801133; hg19: chr1-11856378; COSMIC: COSV64876755; COSMIC: COSV64876755;