rs142617551

Variant names:

• chr1-11794028-T-A
• rs142617551
• NM_005957.5:c.1409A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11794028-T-A
• chr1-11794028-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005957.5(MTHFR):​c.1409A>T​(p.Glu470Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,613,770 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E470Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 7.57
• Publications: 4 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013907462).
• BP6: Variant 1-11794028-T-A is Benign according to our data. Variant chr1-11794028-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 292235.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00175 (266/152220) while in subpopulation NFE AF = 0.00268 (182/67988). AF 95% confidence interval is 0.00236. There are 2 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1409A>T	p.Glu470Val	missense	Exon 9 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.1532A>T	p.Glu511Val	missense	Exon 9 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.1529A>T	p.Glu510Val	missense	Exon 9 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.1409A>T	p.Glu470Val	missense	Exon 9 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.1529A>T	p.Glu510Val	missense	Exon 9 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.1409A>T	p.Glu470Val	missense	Exon 9 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152102 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00156 AC: 392 AN: 251048 AF XY: 0.00151

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00378

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00250 AC: 3656 AN: 1461550 Hom.: 7 Cov.: 31 AF XY: 0.00241 AC XY: 1751 AN XY: 727078

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00440 AC: 234 AN: 53148

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00294 AC: 3267 AN: 1111962

Other (OTH) AF: 0.00179 AC: 108 AN: 60382

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152220 Hom.: 2 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74430

African (AFR) AF: 0.000481 AC: 20 AN: 41544

American (AMR) AF: 0.000850 AC: 13 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00268 AC: 182 AN: 67988

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00207 Hom.: 0

Bravo AF: 0.00137

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00143 AC: 174

EpiCase AF: 0.00185

EpiControl AF: 0.00237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Schizophrenia;C1856061:Homocystinuria due to methylene tetrahydrofolate reductase deficiency;C1866558:Neural tube defects, folate-sensitive;C3160733:Thrombophilia due to thrombin defect (2)
-	-	1	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1)
-	-	1	MTHFR-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.041	D
Polyphen		0.075	B
Vest4		0.53
MVP		0.73
MPC		0.36
ClinPred		0.10	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.35
gMVP		0.62
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142617551; hg19: chr1-11854085;