rs772751654
Variant summary
Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000135.4(FANCA):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,524,084 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 initiator_codon
Scores
Clinical Significance
Conservation
Publications
- Fanconi anemia complementation group AInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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FANCA | NM_000135.4 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 43 | ENST00000389301.8 | NP_000126.2 | |
FANCA | NM_001286167.3 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 43 | NP_001273096.1 | ||
FANCA | NM_001018112.3 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 11 | NP_001018122.1 | ||
FANCA | NM_001351830.2 | c.1A>T | p.Met1? | initiator_codon_variant | Exon 1 of 10 | NP_001338759.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152024Hom.: 0 Cov.: 34 show subpopulations
GnomAD2 exomes AF: 0.00000833 AC: 1AN: 120082 AF XY: 0.0000150 show subpopulations
GnomAD4 exome AF: 0.0000146 AC: 20AN: 1372060Hom.: 0 Cov.: 31 AF XY: 0.0000162 AC XY: 11AN XY: 677814 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152024Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74278 show subpopulations
ClinVar
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:3
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
Fanconi anemia Pathogenic:2
This sequence change affects the initiator methionine of the FANCA mRNA. The next in-frame methionine is located at codon 116. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individual(s) with Fanconi anemia (PMID: 10090479, 16084127, 23898106, 24584348). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553965). For these reasons, this variant has been classified as Pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at