2-47791154-TTGTGTGTGTGTGTG-TTGTGTGTGTGTG

Variant names:

• chr2-47791154-TTG-T
• rs397839804
• NM_000179.3:c.457+52_457+53delTG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000179.3(MSH6):​c.457+52_457+53delTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,120,584 control chromosomes in the GnomAD database, including 231 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (157 hom., cov: 32)
  • Exomes 𝑓: 0.036 (74 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0750
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-47791154-TTG-T is Benign according to our data. Variant chr2-47791154-TTG-T is described in ClinVar as Benign. ClinVar VariationId is 1291001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

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+52_457+53delTG		intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.553+52_553+53delTG		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.463+46_463+47delTG		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+33delTG		intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.457+32_457+33delTG		intron	N/A	ENSP00000405294.1
	MSH6	ENST00000700002.1		c.457+32_457+33delTG		intron	N/A	ENSP00000514750.1

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3645 AN: 150062 Hom.: 156 Cov.: 32

Gnomad AFR AF: 0.0831

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00839

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.000295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0180

GnomAD4 exome AF: 0.0356 AC: 34588 AN: 970428 Hom.: 74 AF XY: 0.0352 AC XY: 17009 AN XY: 483398

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

African (AFR) AF: 0.114 AC: 2807 AN: 24724

American (AMR) AF: 0.0372 AC: 1283 AN: 34464

Ashkenazi Jewish (ASJ) AF: 0.0361 AC: 600 AN: 16614

East Asian (EAS) AF: 0.0264 AC: 768 AN: 29124

South Asian (SAS) AF: 0.0317 AC: 2013 AN: 63442

European-Finnish (FIN) AF: 0.0265 AC: 900 AN: 33912

Middle Eastern (MID) AF: 0.0289 AC: 122 AN: 4228

European-Non Finnish (NFE) AF: 0.0340 AC: 24574 AN: 723578

Other (OTH) AF: 0.0377 AC: 1521 AN: 40342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0244 AC: 3660 AN: 150156 Hom.: 157 Cov.: 32 AF XY: 0.0236 AC XY: 1733 AN XY: 73296

African (AFR) AF: 0.0832 AC: 3422 AN: 41112

American (AMR) AF: 0.00838 AC: 126 AN: 15036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5112

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4718

European-Finnish (FIN) AF: 0.000295 AC: 3 AN: 10178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00101 AC: 68 AN: 67308

Other (OTH) AF: 0.0179 AC: 37 AN: 2068

Alfa AF: 0.0607 Hom.: 1

Bravo AF: 0.0276

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Aug 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.075
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

Other links and lift over

dbSNP: rs397839804; hg19: chr2-48018293;