2-47805601-A-ATT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000179.3(MSH6):​c.3557-5_3557-4dup variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 1,338,350 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0023 ( 6 hom., cov: 28)
Exomes 𝑓: 0.0070 ( 1 hom. )

Consequence

MSH6
NM_000179.3 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.33
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant 2-47805601-A-ATT is Benign according to our data. Variant chr2-47805601-A-ATT is described in ClinVar as [Benign]. Clinvar id is 1328096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00229 (339/147748) while in subpopulation SAS AF= 0.0289 (136/4702). AF 95% confidence interval is 0.025. There are 6 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH6NM_000179.3 linkuse as main transcriptc.3557-5_3557-4dup splice_polypyrimidine_tract_variant, intron_variant ENST00000234420.11 NP_000170.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH6ENST00000234420.11 linkuse as main transcriptc.3557-5_3557-4dup splice_polypyrimidine_tract_variant, intron_variant 1 NM_000179.3 ENSP00000234420 P4P52701-1

Frequencies

GnomAD3 genomes
AF:
0.00229
AC:
338
AN:
147690
Hom.:
6
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.00421
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000338
Gnomad ASJ
AF:
0.000292
Gnomad EAS
AF:
0.000393
Gnomad SAS
AF:
0.0286
Gnomad FIN
AF:
0.000106
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000270
Gnomad OTH
AF:
0.00299
GnomAD4 exome
AF:
0.00697
AC:
8297
AN:
1190602
Hom.:
1
Cov.:
14
AF XY:
0.00747
AC XY:
4474
AN XY:
599304
show subpopulations
Gnomad4 AFR exome
AF:
0.00563
Gnomad4 AMR exome
AF:
0.00206
Gnomad4 ASJ exome
AF:
0.00771
Gnomad4 EAS exome
AF:
0.000237
Gnomad4 SAS exome
AF:
0.0275
Gnomad4 FIN exome
AF:
0.00138
Gnomad4 NFE exome
AF:
0.00600
Gnomad4 OTH exome
AF:
0.00655
GnomAD4 genome
AF:
0.00229
AC:
339
AN:
147748
Hom.:
6
Cov.:
28
AF XY:
0.00268
AC XY:
193
AN XY:
72010
show subpopulations
Gnomad4 AFR
AF:
0.00420
Gnomad4 AMR
AF:
0.000338
Gnomad4 ASJ
AF:
0.000292
Gnomad4 EAS
AF:
0.000394
Gnomad4 SAS
AF:
0.0289
Gnomad4 FIN
AF:
0.000106
Gnomad4 NFE
AF:
0.000270
Gnomad4 OTH
AF:
0.00296

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 06, 2020This alteration is classified as 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BranchPoint Hunter
1.0

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267608102; hg19: chr2-48032740; API