14-64449569-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_005956.4(MTHFD1):c.2404G>A(p.Val802Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,614,190 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_005956.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MTHFD1 | NM_005956.4 | c.2404G>A | p.Val802Ile | missense_variant | Exon 24 of 28 | ENST00000652337.1 | NP_005947.3 | |
MTHFD1 | NM_001364837.1 | c.2404G>A | p.Val802Ile | missense_variant | Exon 24 of 27 | NP_001351766.1 | ||
ZBTB25 | NM_001304508.1 | c.243C>T | p.Asp81Asp | synonymous_variant | Exon 3 of 3 | NP_001291437.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000717 AC: 18AN: 250924Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135658
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461862Hom.: 2 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 727226
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74484
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 802 of the MTHFD1 protein (p.Val802Ile). This variant is present in population databases (rs771687911, gnomAD 0.03%). This missense change has been observed in individual(s) with a positive newborn screening result for MTHFD1-related disease (PMID: 29713328). ClinVar contains an entry for this variant (Variation ID: 1405314). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MTHFD1 protein function with a negative predictive value of 80%. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at