rs144008013
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_020937.4(FANCM):c.5569G>A(p.Val1857Met) variant causes a missense change. The variant allele was found at a frequency of 0.000717 in 1,614,018 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00049 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00074 ( 2 hom. )
Consequence
FANCM
NM_020937.4 missense
NM_020937.4 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 4.93
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 Likely_benign. Variant got -2 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15004778).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCM | NM_020937.4 | c.5569G>A | p.Val1857Met | missense_variant | 21/23 | ENST00000267430.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCM | ENST00000267430.10 | c.5569G>A | p.Val1857Met | missense_variant | 21/23 | 1 | NM_020937.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000493 AC: 75AN: 152148Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000433 AC: 109AN: 251448Hom.: 0 AF XY: 0.000471 AC XY: 64AN XY: 135894
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GnomAD4 exome AF: 0.000740 AC: 1082AN: 1461752Hom.: 2 Cov.: 33 AF XY: 0.000778 AC XY: 566AN XY: 727176
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GnomAD4 genome ? AF: 0.000493 AC: 75AN: 152266Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 38AN XY: 74450
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 06, 2023 | Observed in individuals with a personal and/or family history of breast cancer but also in unaffected controls (PMID: 19737859, 33471991, 35802266); Observed in an individual with cervical cancer and papillary urothelial carcinoma who also had a germline pathogenic variant identified in VHL (PMID: 34628056); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 26596371, 35802266, 19737859, 34628056, 37656691, 34326862) - |
Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2022 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1857 of the FANCM protein (p.Val1857Met). This variant is present in population databases (rs144008013, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 19737859). ClinVar contains an entry for this variant (Variation ID: 408221). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Spermatogenic failure 28;C4748170:Premature ovarian failure 15 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 19, 2021 | - - |
Fanconi anemia, complementation group M Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at