14-64411115-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.11

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]

ACMG classification

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
MTHFD1	NM_005956.4	c.152T>C	p.Leu51Pro	missense_variant	3/28	ENST00000652337.1
MTHFD1	NM_001364837.1	c.152T>C	p.Leu51Pro	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFD1	ENST00000652337.1	c.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

Submissions by phenotype

Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This 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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 21, 2017	- -

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
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

Other links and lift over

dbSNP: rs1555336810; hg19: chr14-64877833;