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GeneBe

1-11790681-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_005957.5(MTHFR):c.1970G>C(p.Ter657SerextTer50) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,786 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. *657*) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 stop_lost

Scores

1
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:1

Conservation

PhyloP100: 0.559
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-11790681-C-G is Pathogenic according to our data. Variant chr1-11790681-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 975602.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}.
BP4
Computational evidence support a benign effect (MetaRNN=0.30170178).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MTHFRNM_005957.5 linkuse as main transcriptc.1970G>C p.Ter657SerextTer50 stop_lost 12/12 ENST00000376590.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MTHFRENST00000376590.9 linkuse as main transcriptc.1970G>C p.Ter657SerextTer50 stop_lost 12/121 NM_005957.5 A1P42898-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251184
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135770
show subpopulations
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1461786
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
727174
show subpopulations
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:
0.0000216
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 26, 2023Variant summary: MTHFR c.1970G>C (p.X657SerextX50) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. MTHFR c.1970G>C (p.X657SerextX50) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 1.2e-05 in 251184 control chromosomes. c.1970G>C has been reported in the homozygous state in brothers with severe methylenetetrahydrofolate reductase deficiency (Tonetti_2003) as well as in a an affected patient with unclassified second allele who had <2% residual MTHFR activity in fibroblasts (Huemer_2016). These data indicate that the variant is likely to be associated with disease. While this variant has not been experimentally tested, a different variant resulting in a similar protein extension (p.*657Argextfs*50) has been reported experimentally to lead to <2% MTHFR activity (Burda_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25736335, 26025547, 12733064). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeFeb 09, 2022This sequence change disrupts the translational stop signal of the MTHFR mRNA. It is expected to extend the length of the MTHFR protein by 50 additional amino acid residues. This variant is present in population databases (rs749490263, gnomAD 0.003%). This protein extension has been observed in individual(s) with severe methylenetetrahydrofolate reductase deficiency (PMID: 12733064). ClinVar contains an entry for this variant (Variation ID: 975602). This variant disrupts the C-terminus of the MTHFR protein. Other variant(s) that disrupt this region (c.1969T>C (p.*657Serext*50)) have been observed in individuals with MTHFR-related conditions (PMID: 25736335). This suggests that this may be a clinically significant region of the protein. 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. -
Neural tube defects, folate-sensitive Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 30, 2023- -
Intellectual disability Benign:1
Likely benign, no assertion criteria providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.88
Cadd
Benign
4.5
Dann
Benign
0.77
Eigen
Uncertain
0.29
Eigen_PC
Benign
-0.057
FATHMM_MKL
Benign
0.065
N
LIST_S2
Benign
0.26
T
MetaRNN
Benign
0.30
T
MutationTaster
Benign
1.0
N;N;N;N
GERP RS
3.0

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749490263; hg19: chr1-11850738; API