chr2-47806597-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The NM_000179.3(MSH6):​c.3947G>T​(p.Gly1316Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1316E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MSH6
NM_000179.3 missense

Scores

8
8
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.11

Publications

0 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

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 16 uncertain in NM_000179.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-47806597-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 490016.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MSH6NM_000179.3 linkc.3947G>T p.Gly1316Val missense_variant Exon 9 of 10 ENST00000234420.11 NP_000170.1 P52701-1Q3SWU9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MSH6ENST00000234420.11 linkc.3947G>T p.Gly1316Val missense_variant Exon 9 of 10 1 NM_000179.3 ENSP00000234420.5 P52701-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461130
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
726874
African (AFR)
AF:
0.00
AC:
0
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44702
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39680
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86244
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52912
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111840
Other (OTH)
AF:
0.00
AC:
0
AN:
60386
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Benign
0.38
.;.;T;D;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
.;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D
MetaSVM
Uncertain
0.34
D
MutationAssessor
Benign
1.9
.;.;.;L;.
PhyloP100
8.1
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-3.9
.;D;.;D;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0060
.;D;.;D;D
Sift4G
Uncertain
0.010
D;D;D;D;D
Polyphen
1.0
.;.;.;D;.
Vest4
0.90
MutPred
0.64
.;.;.;Loss of disorder (P = 0.0436);.;
MVP
0.96
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.95
gMVP
0.86
Mutation Taster
=24/76
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.45
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.45
Position offset: -2

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

Publications

Other links and lift over

dbSNP: rs876661174; hg19: chr2-48033736; API