rs1555363275
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_020937.4(FANCM):c.1946_1958del(p.Pro649LeufsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
FANCM
NM_020937.4 frameshift
NM_020937.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.41
Genes affected
FANCM (HGNC:23168): (FA complementation group M) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group M. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-45167105-ACCAGAGAAGCCTT-A is Pathogenic according to our data. Variant chr14-45167105-ACCAGAGAAGCCTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 559554.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-45167105-ACCAGAGAAGCCTT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCM | NM_020937.4 | c.1946_1958del | p.Pro649LeufsTer17 | frameshift_variant | 11/23 | ENST00000267430.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCM | ENST00000267430.10 | c.1946_1958del | p.Pro649LeufsTer17 | frameshift_variant | 11/23 | 1 | NM_020937.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461598Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727102
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74444
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Spermatogenic failure 28 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 23, 2024 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at