rs758238449
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_021922.3(FANCE):c.206G>A(p.Arg69Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,273,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R69R) has been classified as Likely benign.
Frequency
Consequence
NM_021922.3 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 | UniProt |
---|---|---|---|---|---|---|---|
FANCE | NM_021922.3 | c.206G>A | p.Arg69Gln | missense_variant | 1/10 | ENST00000229769.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCE | ENST00000229769.3 | c.206G>A | p.Arg69Gln | missense_variant | 1/10 | 1 | NM_021922.3 | P1 | |
FANCE | ENST00000696264.1 | c.206G>A | p.Arg69Gln | missense_variant | 1/8 | ||||
FANCE | ENST00000648059.1 | c.206G>A | p.Arg69Gln | missense_variant, NMD_transcript_variant | 1/11 | ||||
FANCE | ENST00000696265.1 | c.206G>A | p.Arg69Gln | missense_variant, NMD_transcript_variant | 1/9 |
Frequencies
GnomAD3 genomes ? AF: 0.000506 AC: 77AN: 152222Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000562 AC: 63AN: 1121042Hom.: 0 Cov.: 30 AF XY: 0.0000502 AC XY: 27AN XY: 537892
GnomAD4 genome ? AF: 0.000505 AC: 77AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35AN XY: 74498
ClinVar
Submissions by phenotype
Fanconi anemia complementation group E Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 07, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 69 of the FANCE protein (p.Arg69Gln). This variant is present in population databases (rs758238449, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with FANCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 471924). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 07, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 12, 2021 | DNA sequence analysis of the FANCE gene demonstrated a sequence change, c.206G>A, in exon 1 that results in an amino acid change, p.Arg69Gln. This sequence change has been described in the gnomAD database with frequency of 0.089% in the African American/African subpopulation (dbSNP rs758238449). The p.Arg69Gln change affects a poorly conserved amino acid residue located in a domain of the FANCE protein that is not known to be functional. The p.Arg69Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in patients with FANCE-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg69Gln change remains unknown at this time. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2022 | 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 - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 14, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at