rs1553333718

Variant names:

• chr2-47806618-T-TTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG
• rs1553333718
• NM_000179.3:c.3969_4001+52dupTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000179.3(MSH6):​c.3969_4001+52dupTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,460,330 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.45
• Publications: 1 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 abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-47806618-T-TTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG is Benign according to our data. Variant chr2-47806618-T-TTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219946.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.3969_4001+52dupTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4065_4097+52dupTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.3975_4007+52dupTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG		intron	N/A	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.3969_4001+52dupTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3316_*3348+52dupTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.3996_4028+52dupTGAGAAGATGAATCAGTCACTACGATTATTTCGGTAACTAACTAACTATAATGGAATTATAACTAACTGACCTTAAGTTTCAAAG		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1460330 Hom.: 0 Cov.: 35 AF XY: 0.0000151 AC XY: 11 AN XY: 726476

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111758

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000329 AC: 5 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74256

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00130453), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome (1)
-	-	1	Lynch syndrome 5 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=3/197	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1553333718; hg19: chr2-48033757;