2-47805601-ATTTTT-ATT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000179.3(MSH6):​c.3557-6_3557-4delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000364 in 1,346,398 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 28)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

MSH6
NM_000179.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.38

Publications

4 publications found
Variant links:
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 abnormalities
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP6
Variant 2-47805601-ATTT-A is Benign according to our data. Variant chr2-47805601-ATTT-A is described in ClinVar as [Likely_benign]. Clinvar id is 3779958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH6NM_000179.3 linkc.3557-6_3557-4delTTT splice_region_variant, intron_variant Intron 6 of 9 ENST00000234420.11 NP_000170.1 P52701-1Q3SWU9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH6ENST00000234420.11 linkc.3557-6_3557-4delTTT splice_region_variant, intron_variant Intron 6 of 9 1 NM_000179.3 ENSP00000234420.5 P52701-1

Frequencies

GnomAD3 genomes
AF:
0.0000542
AC:
8
AN:
147706
Hom.:
0
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.000124
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000450
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000514
AC:
7
AN:
136078
AF XY:
0.0000815
show subpopulations
Gnomad AFR exome
AF:
0.000226
Gnomad AMR exome
AF:
0.0000615
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000137
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000309
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000342
AC:
41
AN:
1198634
Hom.:
0
AF XY:
0.0000365
AC XY:
22
AN XY:
603362
show subpopulations
African (AFR)
AF:
0.000107
AC:
3
AN:
27980
American (AMR)
AF:
0.0000514
AC:
2
AN:
38908
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23512
East Asian (EAS)
AF:
0.0000592
AC:
2
AN:
33788
South Asian (SAS)
AF:
0.0000514
AC:
4
AN:
77750
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47094
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5020
European-Non Finnish (NFE)
AF:
0.0000302
AC:
27
AN:
893716
Other (OTH)
AF:
0.0000590
AC:
3
AN:
50866
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.420
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000541
AC:
8
AN:
147764
Hom.:
0
Cov.:
28
AF XY:
0.0000694
AC XY:
5
AN XY:
72016
show subpopulations
African (AFR)
AF:
0.000123
AC:
5
AN:
40510
American (AMR)
AF:
0.00
AC:
0
AN:
14788
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3434
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5070
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4704
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9422
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
284
European-Non Finnish (NFE)
AF:
0.0000450
AC:
3
AN:
66622
Other (OTH)
AF:
0.00
AC:
0
AN:
2030
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
78
Bravo
AF:
0.0000302

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lynch syndrome 5 Benign:1
Jan 07, 2025
Myriad Genetics, Inc.
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

Lynch syndrome Benign:1
Nov 10, 2022
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
3.4
BranchPoint Hunter
1.0
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs267608102; hg19: chr2-48032740; COSMIC: COSV52274997; COSMIC: COSV52274997; API