2-47805601-AT-A

Variant names:

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

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.3557-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0789 in 1,178,800 control chromosomes in the GnomAD database, including 251 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (222 hom., cov: 28)
  • Exomes 𝑓: 0.086 (29 hom.)
• Consequence: MSH6 NM_000179.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13
• 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-AT-A is Benign according to our data. Variant chr2-47805601-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 89417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.3557-4delT		splice_region_variant, intron_variant	Intron 6 of 9	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.3557-4delT		splice_region_variant, intron_variant	Intron 6 of 9	1	NM_000179.3	ENSP00000234420.5

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4503 AN: 147390 Hom.: 221 Cov.: 28

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00146

Gnomad EAS AF: 0.00413

Gnomad SAS AF: 0.00191

Gnomad FIN AF: 0.00569

Gnomad MID AF: 0.00654

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.0194

GnomAD2 exomes AF: 0.106 AC: 14408 AN: 136078 AF XY: 0.101

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.0793

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.0871

Gnomad NFE exome AF: 0.0815

Gnomad OTH exome AF: 0.0931

GnomAD4 exome AF: 0.0858 AC: 88451 AN: 1031352 Hom.: 29 Cov.: 14 AF XY: 0.0836 AC XY: 43060 AN XY: 514780

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

African (AFR) AF: 0.208 AC: 4998 AN: 24024

American (AMR) AF: 0.117 AC: 3528 AN: 30148

Ashkenazi Jewish (ASJ) AF: 0.0624 AC: 1253 AN: 20096

East Asian (EAS) AF: 0.129 AC: 3103 AN: 24094

South Asian (SAS) AF: 0.0624 AC: 3930 AN: 62970

European-Finnish (FIN) AF: 0.0816 AC: 2973 AN: 36438

Middle Eastern (MID) AF: 0.0512 AC: 232 AN: 4534

European-Non Finnish (NFE) AF: 0.0821 AC: 64511 AN: 785848

Other (OTH) AF: 0.0908 AC: 3923 AN: 43200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0307 AC: 4521 AN: 147448 Hom.: 222 Cov.: 28 AF XY: 0.0294 AC XY: 2109 AN XY: 71848

African (AFR) AF: 0.101 AC: 4078 AN: 40462

American (AMR) AF: 0.0106 AC: 156 AN: 14770

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 5 AN: 3428

East Asian (EAS) AF: 0.00415 AC: 21 AN: 5066

South Asian (SAS) AF: 0.00170 AC: 8 AN: 4700

European-Finnish (FIN) AF: 0.00569 AC: 53 AN: 9318

Middle Eastern (MID) AF: 0.00704 AC: 2 AN: 284

European-Non Finnish (NFE) AF: 0.00238 AC: 158 AN: 66494

Other (OTH) AF: 0.0197 AC: 40 AN: 2026

Alfa AF: 0.0639 Hom.: 78

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:2

Aug 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Apr 08, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Sep 29, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Lynch syndrome 5 Benign:2

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

Computational scores

Source: dbNSFP v4.3

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: COSV52289562; COSMIC: COSV52289562;