rs267608139

Variant names:

• chr2-47806769-TA-T
• rs267608139
• NM_000179.3:c.4002-8delA

Your query was ambiguous. Multiple possible variants found:

• chr2-47806769-TA-T
• chr2-47806769-TA-TAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000179.3(MSH6):​c.4002-8delA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,400,558 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000049 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH6 NM_000179.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.655
• Publications: 3 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 -8 ACMG points.

• BP6: Variant 2-47806769-TA-T is Benign according to our data. Variant chr2-47806769-TA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 416170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH6	NM_000179.3	c.4002-8delA		splice_region_variant, intron_variant	Intron 9 of 9	ENST00000234420.11	NP_000170.1
FBXO11	NM_001190274.2	c.*1348delT		downstream_gene_variant		ENST00000403359.8	NP_001177203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.4002-8delA		splice_region_variant, intron_variant	Intron 9 of 9	1	NM_000179.3	ENSP00000234420.5
FBXO11	ENST00000403359.8	c.*1348delT		downstream_gene_variant		1	NM_001190274.2	ENSP00000384823.4

Frequencies

GnomAD3 genomes AF: 0.0000493 AC: 7 AN: 142082 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000263

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: 0.000326

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000466

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000644 AC: 14 AN: 217244 AF XY: 0.0000673

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000593

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000293 AC: 41 AN: 1400558 Hom.: 0 Cov.: 31 AF XY: 0.0000301 AC XY: 21 AN XY: 697862

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

African (AFR) AF: 0.00 AC: 0 AN: 30732

American (AMR) AF: 0.000195 AC: 8 AN: 40936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25320

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38248

South Asian (SAS) AF: 0.0000613 AC: 5 AN: 81556

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 48910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 0.0000224 AC: 24 AN: 1071282

Other (OTH) AF: 0.0000345 AC: 2 AN: 58030

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000493 AC: 7 AN: 142082 Hom.: 0 Cov.: 30 AF XY: 0.0000434 AC XY: 3 AN XY: 69178

African (AFR) AF: 0.0000263 AC: 1 AN: 37952

American (AMR) AF: 0.00 AC: 0 AN: 14510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3284

East Asian (EAS) AF: 0.00 AC: 0 AN: 4976

South Asian (SAS) AF: 0.00 AC: 0 AN: 4580

European-Finnish (FIN) AF: 0.000326 AC: 3 AN: 9216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000466 AC: 3 AN: 64440

Other (OTH) AF: 0.00 AC: 0 AN: 1942

Alfa AF: 0.000205 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 5 Benign:1

Jan 09, 2025

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Lynch syndrome Benign:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.66

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: rs267608139; hg19: chr2-48033908;