rs45550133

chr1-11801236-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_005957.5(MTHFR):c.400C>T(p.Arg134Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R134H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005957.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38948736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.400C>T	p.Arg134Cys	missense_variant	3/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.400C>T	p.Arg134Cys	missense_variant	3/12	1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251414 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000147 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 03, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 134 of the MTHFR protein (p.Arg134Cys). This variant is present in population databases (rs45550133, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MTHFR-related conditions. ClinVar contains an entry for this variant (Variation ID: 1042820). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects MTHFR function (PMID: 18523009). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 13, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;D;.;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Benign	1.4	L;.;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.0	N;N;N;N;.;.;.;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.014	D;D;D;D;.;.;.;D
Sift4G	Uncertain	0.025	D;D;D;D;.;.;.;.
Polyphen		0.79	P;.;.;P;.;.;.;.
Vest4		0.27
MutPred		0.60		Loss of solvent accessibility (P = 0.0561);.;.;Loss of solvent accessibility (P = 0.0561);.;Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);
MVP		0.91
MPC		0.36
ClinPred		0.12	T
GERP RS		0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs45550133; hg19: chr1-11861293; COSMIC: COSV56737747; COSMIC: COSV56737747;