rs200100285

chr1-11796313-T-Cchr1-11796313-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_005957.5(MTHFR):c.673A>G(p.Ile225Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,613,308 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. I225L) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 1.30

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 4 ACMG points.

• PM1: In a strand (size 3) in uniprot entity MTHR_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005957.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-11796313-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 187879.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.124922335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.673A>G	p.Ile225Val	missense_variant	5/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.673A>G	p.Ile225Val	missense_variant	5/12	1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000529

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 251490 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000316

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000531 AC: 776 AN: 1460976 Hom.: 1 Cov.: 30 AF XY: 0.000493 AC XY: 358 AN XY: 726824

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000663

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74484

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000450 Hom.: 0

Bravo AF: 0.000287

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Schizophrenia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Nutriplexity

Feb 28, 2022

PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. -

Schizophrenia;C1856058:Homocystinuria due to methylene tetrahydrofolate reductase deficiency;C1866558:Neural tube defects, folate-sensitive;C3160733:Thrombophilia due to thrombin defect Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 27, 2022

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 225 of the MTHFR protein (p.Ile225Val). This variant is present in population databases (rs200100285, gnomAD 0.03%). 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: 1369489). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	13
Dann	Benign	0.89
DEOGEN2	Uncertain	0.64	D;.;.;D;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.1	L;.;.;L;.;.;.
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.54	N;N;N;N;.;.;.
REVEL	Benign	0.22
Sift	Benign	0.19	T;T;T;T;.;.;.
Sift4G	Benign	0.26	T;T;T;T;.;.;.
Polyphen		0.17	B;.;.;B;.;.;.
Vest4		0.16
MVP		0.59
MPC		0.27
ClinPred		0.015	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.66

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: rs200100285; hg19: chr1-11856370;