2-47804908-A-G

Variant names:

• chr2-47804908-A-G
• rs267608098
• NM_000179.3:c.3439-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000179.3(MSH6):​c.3439-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000271401: This variant was corroborated by a functional study using patient RNA that shows that this variant causes out-of-frame skipping of exon 6 (Thompson 2013 PMID:22949379).; SCV004822616: An RNA functional study using RNA derived from a carrier individual has reported that this variant causes out-of-frame skipping of exon 6 (PMID:22949379).; SCV000185356: RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This alteration was predicted to cause skipping of coding exon 6, and a deletion of this region in yeast resulted in complete loss of MSH6 function (Kolodner, 1999).; SCV000537629: An RNA functional study using RNA derived from a carrier individual has reported that this variant causes out-of-frame skipping of exon 6 (PMID:22949379).; SCV000888274: The variant also showed deleterious effects on protein function in a yeast-based complementation assay (PMID:10537275 (1999)).; SCV000253678: Studies have shown that disruption of this splice site results in exon 6 skipping, and produces a non-functional protein and/or introduces a premature termination codon (internal data).; SCV000695866: The variant was reported to affect mRNA splicing (Kolodner_1999).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH6 NM_000179.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:19
• Conservation: PhyloP100: 8.92
• Publications: 11 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

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000271401: This variant was corroborated by a functional study using patient RNA that shows that this variant causes out-of-frame skipping of exon 6 (Thompson 2013 PMID: 22949379).; SCV004822616: An RNA functional study using RNA derived from a carrier individual has reported that this variant causes out-of-frame skipping of exon 6 (PMID: 22949379).; SCV000185356: RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This alteration was predicted to cause skipping of coding exon 6, and a deletion of this region in yeast resulted in complete loss of MSH6 function (Kolodner, 1999).; SCV000537629: An RNA functional study using RNA derived from a carrier individual has reported that this variant causes out-of-frame skipping of exon 6 (PMID: 22949379).; SCV000888274: The variant also showed deleterious effects on protein function in a yeast-based complementation assay (PMID: 10537275 (1999)).; SCV000253678: Studies have shown that disruption of this splice site results in exon 6 skipping, and produces a non-functional protein and/or introduces a premature termination codon (internal data).; SCV000695866: The variant was reported to affect mRNA splicing (Kolodner_1999).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47804908-A-G is Pathogenic according to our data. Variant chr2-47804908-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 89391.Status of the report is reviewed_by_expert_panel, 3 stars.

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.3439-2A>G		splice_acceptor intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.3535-2A>G		splice_acceptor intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.3445-2A>G		splice_acceptor 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.3439-2A>G		splice_acceptor intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*2786-2A>G		splice_acceptor intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.3466-2A>G		splice_acceptor intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459678 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726366

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110030

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000696 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
3	-	-	Hereditary cancer-predisposing syndrome (3)
3	-	-	Lynch syndrome (3)
2	-	-	Lynch syndrome 5 (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Carcinoma of colon (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	MSH6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.9
GERP RS		5.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: 2

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

Other links and lift over

dbSNP: rs267608098; hg19: chr2-48032047;