2-47791154-TTGTGTGTGTGTGTG-TTGTGTGTG

Variant names:

• chr2-47791154-TTGTGTG-T
• rs397839804
• NM_000179.3:c.457+48_457+53delTGTGTG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_000179.3(MSH6):​c.457+48_457+53delTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,317,728 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.908
• 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 abnormalities

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 2-47791154-TTGTGTG-T is Benign according to our data. Variant chr2-47791154-TTGTGTG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1697906.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.457+48_457+53delTGTGTG		intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.553+48_553+53delTGTGTG		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.463+42_463+47delTGTGTG		intron	N/A	NP_001393742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.457+32_457+37delTGTGTG		intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.457+32_457+37delTGTGTG		intron	N/A	ENSP00000405294.1
	MSH6	ENST00000700002.1		c.457+32_457+37delTGTGTG		intron	N/A	ENSP00000514750.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150458 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000454 AC: 53 AN: 1167270 Hom.: 0 AF XY: 0.0000512 AC XY: 30 AN XY: 586384

African (AFR) AF: 0.00 AC: 0 AN: 27742

American (AMR) AF: 0.0000490 AC: 2 AN: 40822

Ashkenazi Jewish (ASJ) AF: 0.0000451 AC: 1 AN: 22166

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37332

South Asian (SAS) AF: 0.0000386 AC: 3 AN: 77804

European-Finnish (FIN) AF: 0.0000217 AC: 1 AN: 46004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4940

European-Non Finnish (NFE) AF: 0.0000500 AC: 43 AN: 860754

Other (OTH) AF: 0.0000402 AC: 2 AN: 49706

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150458 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73406

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

African (AFR) AF: 0.0000244 AC: 1 AN: 41040

American (AMR) AF: 0.00 AC: 0 AN: 15044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67480

Other (OTH) AF: 0.00 AC: 0 AN: 2056

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.91

Splicing

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

Other links and lift over

dbSNP: rs397839804; hg19: chr2-48018293;