rs1553187509

Variant names:

• chr1-11801399-C-A
• rs1553187509
• NM_005957.5:c.237G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_005957.5(MTHFR):​c.237G>T​(p.Arg79Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTHFR NM_005957.5 missense, splice_region
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.35
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-11801399-C-A is Pathogenic according to our data. Variant chr1-11801399-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 522640.Status of the report is criteria_provided_single_submitter, 1 stars.

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.237G>T	p.Arg79Ser	missense splice_region	Exon 3 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.360G>T	p.Arg120Ser	missense splice_region	Exon 3 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.357G>T	p.Arg119Ser	missense splice_region	Exon 3 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.237G>T	p.Arg79Ser	missense splice_region	Exon 3 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.357G>T	p.Arg119Ser	missense splice_region	Exon 3 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.237G>T	p.Arg79Ser	missense splice_region	Exon 3 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.051	T
Polyphen		0.94	P
Vest4		0.71
MutPred		0.79		Loss of MoRF binding (P = 0.0745)
MVP		0.99
MPC		0.76
ClinPred		0.97	D
GERP RS		3.6
Varity_R		0.95
gMVP		0.82
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.59		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553187509; hg19: chr1-11861456;