chr14-64411115-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_005956.4(MTHFD1):​c.152T>C​(p.Leu51Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MTHFD1
NM_005956.4 missense

Scores

5
8
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.11
Variant links:
Genes affected
MTHFD1 (HGNC:7432): (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1) This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.839
PP5
Variant 14-64411115-T-C is Pathogenic according to our data. Variant chr14-64411115-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 446309.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MTHFD1NM_005956.4 linkuse as main transcriptc.152T>C p.Leu51Pro missense_variant 3/28 ENST00000652337.1
MTHFD1NM_001364837.1 linkuse as main transcriptc.152T>C p.Leu51Pro missense_variant 3/27

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MTHFD1ENST00000652337.1 linkuse as main transcriptc.152T>C p.Leu51Pro missense_variant 3/28 NM_005956.4 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 21, 2017- -
Likely pathogenic, criteria provided, single submittercurationSIB Swiss Institute of BioinformaticsOct 15, 2018This variant is interpreted as Likely Pathogenic, for Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia, autosomal recessive. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/27707659). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1-Supporting => PM1 downgraded in strength to Supporting (https://www.uniprot.org/uniprot/P11586). PM3-Supporting => PM3 downgraded in strength to Supporting (https://www.ncbi.nlm.nih.gov/pubmed/27707659). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
27
DANN
Uncertain
1.0
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
.;.;D
M_CAP
Benign
0.043
D
MetaRNN
Pathogenic
0.84
D;D;D
MetaSVM
Benign
-0.96
T
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-2.4
N;.;.
REVEL
Uncertain
0.38
Sift
Uncertain
0.012
D;.;.
Sift4G
Uncertain
0.016
D;D;D
Polyphen
0.92
P;.;.
Vest4
0.87
MutPred
0.84
Loss of stability (P = 0.0202);Loss of stability (P = 0.0202);.;
MVP
0.66
MPC
1.5
ClinPred
0.99
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1555336810; hg19: chr14-64877833; API