2-47805614-TA-TAA
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PVS1_ModeratePM2BP6_Moderate
The NM_000179.3(MSH6):c.3557-2dupA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
MSH6
NM_000179.3 splice_acceptor, intron
NM_000179.3 splice_acceptor, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.34
Publications
0 publications found
Genes affected
MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]
FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]
FBXO11 Gene-Disease associations (from GenCC):
- intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
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ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.022042615 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 0 (no position change), new splice context is: tgatttttttttttttaaAGgtg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 2-47805614-T-TA is Benign according to our data. Variant chr2-47805614-T-TA is described in ClinVar as Likely_benign. ClinVar VariationId is 89414.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MSH6 | TSL:1 MANE Select | c.3557-2dupA | splice_acceptor intron | N/A | ENSP00000234420.5 | P52701-1 | |||
| MSH6 | TSL:1 | n.*2904-2dupA | splice_acceptor intron | N/A | ENSP00000405294.1 | F8WAX8 | |||
| MSH6 | c.3584-2dupA | splice_acceptor intron | N/A | ENSP00000606570.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1446028Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 720234
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1446028
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
720234
African (AFR)
AF:
AC:
0
AN:
33094
American (AMR)
AF:
AC:
0
AN:
44648
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26036
East Asian (EAS)
AF:
AC:
0
AN:
39584
South Asian (SAS)
AF:
AC:
0
AN:
85702
European-Finnish (FIN)
AF:
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
AC:
0
AN:
5688
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1098082
Other (OTH)
AF:
AC:
0
AN:
59794
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
ClinVar submissions
View on ClinVar Significance:Likely benign
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
-
1
Hereditary nonpolyposis colorectal neoplasms (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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