2-47805601-ATTTTT-ATTTTTTT

Variant names:

• chr2-47805601-A-ATT
• rs267608102
• NM_000179.3:c.3557-5_3557-4dupTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000179.3(MSH6):​c.3557-5_3557-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 1,338,350 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). The gene MSH6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0023 (6 hom., cov: 28)
  • Exomes 𝑓: 0.0070 (1 hom.)
• Consequence: MSH6 NM_000179.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.33
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for MSH6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-47805601-A-ATT is Benign according to our data. Variant chr2-47805601-A-ATT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1328096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00229 (339/147748) while in subpopulation SAS AF = 0.0289 (136/4702). AF 95% confidence interval is 0.025. There are 6 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

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.3557-5_3557-4dupTT		splice_region intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.3653-5_3653-4dupTT		splice_region intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.3563-5_3563-4dupTT		splice_region 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.3557-5_3557-4dupTT		splice_region intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*2904-5_*2904-4dupTT		splice_region intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.3584-5_3584-4dupTT		splice_region intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 338 AN: 147690 Hom.: 6 Cov.: 28

Gnomad AFR AF: 0.00421

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000338

Gnomad ASJ AF: 0.000292

Gnomad EAS AF: 0.000393

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.000106

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000270

Gnomad OTH AF: 0.00299

GnomAD2 exomes AF: 0.00734 AC: 999 AN: 136078 AF XY: 0.00887

Gnomad AFR exome AF: 0.00801

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.000684

Gnomad FIN exome AF: 0.000695

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00697 AC: 8297 AN: 1190602 Hom.: 1 Cov.: 14 AF XY: 0.00747 AC XY: 4474 AN XY: 599304

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

African (AFR) AF: 0.00563 AC: 157 AN: 27906

American (AMR) AF: 0.00206 AC: 80 AN: 38786

Ashkenazi Jewish (ASJ) AF: 0.00771 AC: 180 AN: 23338

East Asian (EAS) AF: 0.000237 AC: 8 AN: 33712

South Asian (SAS) AF: 0.0275 AC: 2121 AN: 77030

European-Finnish (FIN) AF: 0.00138 AC: 65 AN: 46940

Middle Eastern (MID) AF: 0.00581 AC: 29 AN: 4988

European-Non Finnish (NFE) AF: 0.00600 AC: 5326 AN: 887338

Other (OTH) AF: 0.00655 AC: 331 AN: 50564

⚠️ 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: 0.00229 AC: 339 AN: 147748 Hom.: 6 Cov.: 28 AF XY: 0.00268 AC XY: 193 AN XY: 72010

African (AFR) AF: 0.00420 AC: 170 AN: 40508

American (AMR) AF: 0.000338 AC: 5 AN: 14788

Ashkenazi Jewish (ASJ) AF: 0.000292 AC: 1 AN: 3430

East Asian (EAS) AF: 0.000394 AC: 2 AN: 5070

South Asian (SAS) AF: 0.0289 AC: 136 AN: 4702

European-Finnish (FIN) AF: 0.000106 AC: 1 AN: 9418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000270 AC: 18 AN: 66620

Other (OTH) AF: 0.00296 AC: 6 AN: 2028

Alfa AF: 0.00358 Hom.: 78

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Lynch syndrome (1)
-	-	1	Lynch syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs267608102; hg19: chr2-48032740;