rs45590836

Positions:

• chr1-11791216-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005957.5(MTHFR):​c.1743G>A​(p.Met581Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.81

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22037587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.1743G>A	p.Met581Ile	missense_variant	11/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.1743G>A	p.Met581Ile	missense_variant	11/12	1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251462 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000451 AC: 66 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152166 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000739 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 13, 2021	This sequence change replaces methionine with isoleucine at codon 581 of the MTHFR protein (p.Met581Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs45590836, ExAC 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive severe MTHFR deficiency (PMID: 12840091). This variant is also known as c.1755G>A. ClinVar contains an entry for this variant (Variation ID: 3527). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 03, 2003	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;T;.;.;.
Eigen	Benign	-0.031
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.29	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	2.0	M;.;.;M;.;.;.
MutationTaster	Benign	0.99	A;A;A;A
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N;N;N;N;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.44	T;T;T;T;.;.;.
Sift4G	Benign	0.46	T;T;T;T;.;.;.
Polyphen		0.0010	B;.;.;B;.;.;.
Vest4		0.81
MutPred		0.47		Gain of glycosylation at S579 (P = 0.0999);.;.;Gain of glycosylation at S579 (P = 0.0999);.;Gain of glycosylation at S579 (P = 0.0999);.;
MVP		0.53
MPC		0.29
ClinPred		0.18	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.61

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: rs45590836; hg19: chr1-11851273; COSMIC: COSV100453860; COSMIC: COSV100453860;