2-47805601-ATTTTT-AT

Position:

• chr2-47805601-ATTTTT-AT

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000179.3(MSH6):​c.3557-7_3557-4delTTTT 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_000179.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.38

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 419602.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr2-47805601-ATTTT-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3557-7_3557-4delTTTT		splice_region_variant, intron_variant		ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3557-7_3557-4delTTTT		splice_region_variant, intron_variant		1	NM_000179.3	ENSP00000234420.5

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

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

Gnomad4 AFR exome AF: 0.0000715

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000296

Gnomad4 SAS exome AF: 0.0000257

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000300

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 21, 2016	Variant summary: The MSH6 c.3557-7_3557-4delTTTT variant involves the deletion of multiple non-conserved intronic nucleotides. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/90548 control chromosomes at a frequency of 0.0000221, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable clinical diagnostic laboratories. The variant has been cited by one database with a classification of "UV." Because of the absence of clinical information and the lack of functional studies, the variant is classified as a Variant of Uncertain Significance (VUS), until additional information becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs267608102; hg19: chr2-48032740;