chr2-47805601-ATTTT-A

Variant names:

• chr2-47805601-ATTTT-A
• rs267608102
• NM_000179.3:c.3557-7_3557-4delTTTT

Variant summary

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

The NM_001406795.1(MSH6):​c.3653-7_3653-4delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,346,590 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: MSH6 NM_001406795.1 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.38
• Publications: 4 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 -1 ACMG points.

• BP6: Variant 2-47805601-ATTTT-A is Benign according to our data. Variant chr2-47805601-ATTTT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 419602.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406795.1. 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.3557-7_3557-4delTTTT		splice_region intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.3653-7_3653-4delTTTT		splice_region intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.3563-7_3563-4delTTTT		splice_region 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.3557-7_3557-4delTTTT		splice_region intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*2904-7_*2904-4delTTTT		splice_region intron	N/A	ENSP00000405294.1
	MSH6	ENST00000936511.1		c.3584-7_3584-4delTTTT		splice_region intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 147706 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

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: 0.0000300

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000441 AC: 6 AN: 136078 AF XY: 0.0000679

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000284 AC: 34 AN: 1198884 Hom.: 0 AF XY: 0.0000331 AC XY: 20 AN XY: 603464

African (AFR) AF: 0.0000715 AC: 2 AN: 27990

American (AMR) AF: 0.00 AC: 0 AN: 38914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23514

East Asian (EAS) AF: 0.0000296 AC: 1 AN: 33792

South Asian (SAS) AF: 0.0000257 AC: 2 AN: 77760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5020

European-Non Finnish (NFE) AF: 0.0000324 AC: 29 AN: 893918

Other (OTH) AF: 0.00 AC: 0 AN: 50878

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 147706 Hom.: 0 Cov.: 28 AF XY: 0.0000139 AC XY: 1 AN XY: 71938

African (AFR) AF: 0.00 AC: 0 AN: 40418

American (AMR) AF: 0.00 AC: 0 AN: 14772

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000300 AC: 2 AN: 66630

Other (OTH) AF: 0.00 AC: 0 AN: 2010

Alfa AF: 0.00 Hom.: 78

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Mismatch repair cancer syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267608102; hg19: chr2-48032740;