1-11794419-T-G

Variant names:

• chr1-11794419-T-G
• rs1801131
• NM_005957.5:c.1286A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_005957.5(MTHFR):​c.1286A>C​(p.Glu429Ala) variant causes a missense change. The variant allele was found at a frequency of 0.303 in 1,613,542 control chromosomes in the GnomAD database, including 76,973 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E429V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (5754 hom., cov: 31)
  • Exomes 𝑓: 0.31 (71219 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1 U:1 B:19 O:2
• Conservation: PhyloP100: 3.76
• Publications: 3404 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 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, 6 uncertain in NM_005957.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029579103).
• BP6: Variant 1-11794419-T-G is Benign according to our data. Variant chr1-11794419-T-G is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 3521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

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.1286A>C	p.Glu429Ala	missense	Exon 8 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.1409A>C	p.Glu470Ala	missense	Exon 8 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.1406A>C	p.Glu469Ala	missense	Exon 8 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.1286A>C	p.Glu429Ala	missense	Exon 8 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.1406A>C	p.Glu469Ala	missense	Exon 8 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.1286A>C	p.Glu429Ala	missense	Exon 8 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 40003 AN: 151880 Hom.: 5754 Cov.: 31

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.271

GnomAD2 exomes AF: 0.289 AC: 72672 AN: 251462 AF XY: 0.301

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.296

GnomAD4 exome AF: 0.307 AC: 449260 AN: 1461544 Hom.: 71219 Cov.: 49 AF XY: 0.311 AC XY: 226409 AN XY: 727098

African (AFR) AF: 0.157 AC: 5264 AN: 33472

American (AMR) AF: 0.167 AC: 7482 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7625 AN: 26136

East Asian (EAS) AF: 0.205 AC: 8131 AN: 39698

South Asian (SAS) AF: 0.411 AC: 35461 AN: 86250

European-Finnish (FIN) AF: 0.314 AC: 16754 AN: 53404

Middle Eastern (MID) AF: 0.373 AC: 2152 AN: 5768

European-Non Finnish (NFE) AF: 0.313 AC: 347994 AN: 1111708

Other (OTH) AF: 0.305 AC: 18397 AN: 60384

GnomAD4 genome AF: 0.263 AC: 40027 AN: 151998 Hom.: 5754 Cov.: 31 AF XY: 0.265 AC XY: 19654 AN XY: 74288

African (AFR) AF: 0.167 AC: 6937 AN: 41452

American (AMR) AF: 0.207 AC: 3162 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1030 AN: 3468

East Asian (EAS) AF: 0.221 AC: 1135 AN: 5144

South Asian (SAS) AF: 0.408 AC: 1962 AN: 4812

European-Finnish (FIN) AF: 0.328 AC: 3460 AN: 10554

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.316 AC: 21468 AN: 67966

Other (OTH) AF: 0.270 AC: 569 AN: 2108

Alfa AF: 0.297 Hom.: 25769

Bravo AF: 0.246

TwinsUK AF: 0.325 AC: 1205

ALSPAC AF: 0.313 AC: 1207

ESP6500AA AF: 0.155 AC: 683

ESP6500EA AF: 0.313 AC: 2693

ExAC AF: 0.295 AC: 35807

Asia WGS AF: 0.304 AC: 1057 AN: 3478

EpiCase AF: 0.314

EpiControl AF: 0.309

ClinVar

ClinVar submissions

Significance: Benign/Likely benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
1	-	5	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (6)
-	-	3	not provided (4)
-	1	-	Gastrointestinal stromal tumor (1)
-	-	1	MTHFR THERMOLABILE POLYMORPHISM (1)
-	-	1	MTHFR-related disorder (1)
-	-	1	Neural tube defects, folate-sensitive (1)
-	-	1	Schizophrenia;C1856061:Homocystinuria due to methylene tetrahydrofolate reductase deficiency;C1866558:Neural tube defects, folate-sensitive;C3160733:Thrombophilia due to thrombin defect (1)
-	-	-	Schizophrenia, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.8
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.20
Sift	Benign	0.10	T
Sift4G	Benign	0.20	T
Polyphen		0.021	B
Vest4		0.21
MPC		0.28
ClinPred		0.019	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.21
gMVP		0.58
Mutation Taster		=91/9	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: rs1801131; hg19: chr1-11854476; COSMIC: COSV57171183; COSMIC: COSV57171183;