2-47805601-ATTTTT-ATTTTTT

Variant names:

• chr2-47805601-A-AT
• rs267608102
• NM_000179.3:c.3557-4dupT

Variant summary

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

The ENST00000234420.11(MSH6):​c.3557-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 147,526 control chromosomes in the GnomAD database, including 1,781 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1781 hom., cov: 28)
  • Exomes 𝑓: 0.27 (1504 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH6 ENST00000234420.11 splice_region, intron
• Clinical Significance: Benign reviewed by expert panel B:16
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

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

• BP6: Variant 2-47805601-A-AT is Benign according to our data. Variant chr2-47805601-A-AT is described in ClinVar as Benign. ClinVar VariationId is 89418.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000234420.11. 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.3557-4dupT		splice_region intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.3653-4dupT		splice_region intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.3563-4dupT		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.3557-4dupT		splice_region intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*2904-4dupT		splice_region intron	N/A	ENSP00000405294.1
	MSH6	ENST00000699999.1		n.4227dupT		non_coding_transcript_exon	Exon 6 of 9

Frequencies

GnomAD3 genomes AF: 0.148 AC: 21845 AN: 147468 Hom.: 1779 Cov.: 28

Gnomad AFR AF: 0.0751

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0350

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.153

GnomAD2 exomes AF: 0.297 AC: 40365 AN: 136078 AF XY: 0.307

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.156

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.339

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.268 AC: 284923 AN: 1061714 Hom.: 1504 Cov.: 14 AF XY: 0.268 AC XY: 142604 AN XY: 531538

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

African (AFR) AF: 0.153 AC: 3778 AN: 24770

American (AMR) AF: 0.185 AC: 6006 AN: 32378

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 6886 AN: 20664

East Asian (EAS) AF: 0.116 AC: 3002 AN: 25826

South Asian (SAS) AF: 0.271 AC: 18080 AN: 66604

European-Finnish (FIN) AF: 0.218 AC: 8513 AN: 39020

Middle Eastern (MID) AF: 0.290 AC: 1354 AN: 4666

European-Non Finnish (NFE) AF: 0.280 AC: 225208 AN: 803036

Other (OTH) AF: 0.270 AC: 12096 AN: 44750

⚠️ 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: 0.148 AC: 21852 AN: 147526 Hom.: 1781 Cov.: 28 AF XY: 0.148 AC XY: 10670 AN XY: 71868

African (AFR) AF: 0.0751 AC: 3040 AN: 40486

American (AMR) AF: 0.143 AC: 2110 AN: 14754

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 999 AN: 3428

East Asian (EAS) AF: 0.0349 AC: 177 AN: 5066

South Asian (SAS) AF: 0.202 AC: 950 AN: 4698

European-Finnish (FIN) AF: 0.137 AC: 1276 AN: 9342

Middle Eastern (MID) AF: 0.232 AC: 66 AN: 284

European-Non Finnish (NFE) AF: 0.191 AC: 12691 AN: 66538

Other (OTH) AF: 0.156 AC: 317 AN: 2030

Alfa AF: 0.147 Hom.: 78

Bravo AF: 0.140

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 (1)
-	-	1	Familial cancer of breast (1)
-	-	1	Lynch syndrome (1)
-	-	1	Lynch syndrome 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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: rs267608102; hg19: chr2-48032740; COSMIC: COSV52280258; COSMIC: COSV52280258;