14-45173161-G-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The ENST00000267430.10(FANCM):c.2267G>T(p.Arg756Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R756H) has been classified as Likely benign.
Frequency
Consequence
ENST00000267430.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCM | NM_020937.4 | c.2267G>T | p.Arg756Leu | missense_variant | 13/23 | ENST00000267430.10 | NP_065988.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FANCM | ENST00000267430.10 | c.2267G>T | p.Arg756Leu | missense_variant | 13/23 | 1 | NM_020937.4 | ENSP00000267430 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251202Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135758
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461338Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727012
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 16, 2023 | The c.2267G>T (p.R756L) alteration is located in exon 13 (coding exon 13) of the FANCM gene. This alteration results from a G to T substitution at nucleotide position 2267, causing the arginine (R) at amino acid position 756 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 10, 2023 | This variant is present in population databases (rs142763060, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 756 of the FANCM protein (p.Arg756Leu). This variant has not been reported in the literature in individuals affected with FANCM-related conditions. ClinVar contains an entry for this variant (Variation ID: 856163). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 | Dec 16, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 14, 2024 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26759717, 26689913, 29641532) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at