14-45189042-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_020937.4(FANCM):āc.5020A>Gā(p.Ser1674Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000688 in 1,613,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. S1674S) has been classified as Likely benign.
Frequency
Consequence
NM_020937.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCM | NM_020937.4 | c.5020A>G | p.Ser1674Gly | missense_variant | 20/23 | ENST00000267430.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCM | ENST00000267430.10 | c.5020A>G | p.Ser1674Gly | missense_variant | 20/23 | 1 | NM_020937.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000460 AC: 70AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000876 AC: 22AN: 251008Hom.: 0 AF XY: 0.0000884 AC XY: 12AN XY: 135706
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461632Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 727130
GnomAD4 genome AF: 0.000460 AC: 70AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74380
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a pediatric patient with acute megakaryoblastic leukemia (Zhang et al., 2015); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26580448) - |
Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 15, 2023 | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1674 of the FANCM protein (p.Ser1674Gly). This variant is present in population databases (rs140499872, gnomAD 0.1%). This missense change has been observed in individual(s) with acute megakaryoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 526313). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 30, 2021 | - - |
Spermatogenic failure 28 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 20, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at