rs781065280
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_005956.4(MTHFD1):c.727+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,607,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_005956.4 splice_donor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MTHFD1 | NM_005956.4 | c.727+1G>A | splice_donor_variant | ENST00000652337.1 | |||
MTHFD1 | NM_001364837.1 | c.727+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MTHFD1 | ENST00000652337.1 | c.727+1G>A | splice_donor_variant | NM_005956.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251104Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135702
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1454946Hom.: 0 Cov.: 29 AF XY: 0.00000966 AC XY: 7AN XY: 724360
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 21, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 20, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 446302). Disruption of this splice site has been observed in individual(s) with clinical features of methylenetetrahydrofolate dehydrogenase 1 deficiency (PMID: 21813566, 23296427). This variant is present in population databases (rs781065280, gnomAD 0.04%). This sequence change affects a donor splice site in intron 8 of the MTHFD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MTHFD1 are known to be pathogenic (PMID: 21813566, 25633902). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at