NM_005957.5:c.379C>T

Variant names:

• chr1-11801257-G-A
• rs769381688
• NM_005957.5:c.379C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_005957.5(MTHFR):​c.379C>T​(p.His127Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.20

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 1-11801257-G-A is Pathogenic according to our data. Variant chr1-11801257-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187873.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.379C>T	p.His127Tyr	missense_variant	Exon 3 of 12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.379C>T	p.His127Tyr	missense_variant	Exon 3 of 12	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251448 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:2

-

University Children's Hospital, University of Zurich

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jul 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MTHFR c.379C>T (p.His127Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251448 control chromosomes. c.379C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with MTHFR deficiency (e.g. Mercimek-Mahmutoglu_2015, Burda_2015). These data indicate that the variant may be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g. Weile_2021). The following publications have been ascertained in the context of this evaluation (PMID: 25736335, 25758715, 34214447). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;D;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	.;D;.;D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;H;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;.;.;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;.;.;.;.
Polyphen		1.0	D;.;.;D;.;.;.;.
Vest4		0.97
MutPred		0.92		Loss of catalytic residue at L126 (P = 0.2509);.;.;Loss of catalytic residue at L126 (P = 0.2509);.;Loss of catalytic residue at L126 (P = 0.2509);Loss of catalytic residue at L126 (P = 0.2509);Loss of catalytic residue at L126 (P = 0.2509);
MVP		0.99
MPC		1.0
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

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: rs769381688; hg19: chr1-11861314; COSMIC: COSV100412283; COSMIC: COSV100412283;