chr9-35077009-G-T
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_004629.2(FANCG):c.739C>A(p.Gln247Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,614,206 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00094 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000090 ( 0 hom. )
Consequence
FANCG
NM_004629.2 missense
NM_004629.2 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 3.37
Genes affected
FANCG (HGNC:3588): (FA complementation group G) 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 G. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.013439447).
BP6
?
Variant 9-35077009-G-T is Benign according to our data. Variant chr9-35077009-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435153.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000939 (143/152314) while in subpopulation AFR AF= 0.00325 (135/41568). AF 95% confidence interval is 0.0028. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCG | NM_004629.2 | c.739C>A | p.Gln247Lys | missense_variant | 6/14 | ENST00000378643.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCG | ENST00000378643.8 | c.739C>A | p.Gln247Lys | missense_variant | 6/14 | 1 | NM_004629.2 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000933 AC: 142AN: 152196Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000286 AC: 72AN: 251472Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135910
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GnomAD4 exome AF: 0.0000903 AC: 132AN: 1461892Hom.: 0 Cov.: 34 AF XY: 0.0000674 AC XY: 49AN XY: 727246
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GnomAD4 genome ? AF: 0.000939 AC: 143AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75AN XY: 74486
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Fanconi anemia complementation group G Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 26, 2022 | The FANCG c.739C>A (p.Gln247Lys) missense change has a maximum subpopulation frequency of 0.36% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported as heterozygous in at least one individual with a head or neck squamous cell carcinoma (PMID: 28678401). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 07, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Fanconi anemia Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 26, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 16, 2016 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2019 | This variant is associated with the following publications: (PMID: 28678401) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
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
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
P
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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