16-89816614-A-T
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000135.4(FANCA):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,372,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000135.4 start_lost
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.2T>A | p.Met1? | start_lost | Exon 1 of 43 | ENST00000389301.8 | NP_000126.2 | |
FANCA | NM_001286167.3 | c.2T>A | p.Met1? | start_lost | Exon 1 of 43 | NP_001273096.1 | ||
FANCA | NM_001018112.3 | c.2T>A | p.Met1? | start_lost | Exon 1 of 11 | NP_001018122.1 | ||
FANCA | NM_001351830.2 | c.2T>A | p.Met1? | start_lost | Exon 1 of 10 | NP_001338759.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 exomes AF: 0.00000829 AC: 1AN: 120628Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67104
GnomAD4 exome AF: 7.29e-7 AC: 1AN: 1372296Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 677952
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:2
- -
- -
Fanconi anemia Pathogenic:1
Variant summary: FANCA c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream Met is p.Met116. A different start-lost variant has been classified as Pathogenic by Labcorp (p.Met1Thr (c.2T>C)). Two of two in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 120628 control chromosomes. c.2T>A has been reported in the homozygous and compound heterozygous state in the literature in multiple individuals affected with Fanconi Anemia (example, DeRocco_2014, Joshi_2023, Monies_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24584348, 36894310, 31130284). ClinVar contains an entry for this variant (Variation ID: 556239). Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at