rs545466048

Variant names:

• chr2-47806769-T-A
• rs545466048
• NM_000179.3:c.4002-10T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47806769-T-A
• chr2-47806769-T-C
• chr2-47806769-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000179.3(MSH6):​c.4002-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,542,738 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Scores: Splicing: ADA: 0.009428
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:13
• Conservation: PhyloP100: -2.24
• Publications: 7 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-47806769-T-A is Benign according to our data. Variant chr2-47806769-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 89507.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000295 (42/142178) while in subpopulation EAS AF = 0.00222 (11/4962). AF 95% confidence interval is 0.00124. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.4002-10T>A		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4098-10T>A		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.4008-10T>A		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.4002-10T>A		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3349-10T>A		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.4029-10T>A		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 42 AN: 142084 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000790

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000620

Gnomad ASJ AF: 0.00122

Gnomad EAS AF: 0.00221

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000233

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000276 AC: 60 AN: 217244 AF XY: 0.000328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000194

Gnomad ASJ exome AF: 0.00152

Gnomad EAS exome AF: 0.000448

Gnomad FIN exome AF: 0.000356

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000379

GnomAD4 exome AF: 0.000365 AC: 511 AN: 1400560 Hom.: 2 Cov.: 31 AF XY: 0.000374 AC XY: 261 AN XY: 697862

African (AFR) AF: 0.0000976 AC: 3 AN: 30740

American (AMR) AF: 0.000220 AC: 9 AN: 40944

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 40 AN: 25316

East Asian (EAS) AF: 0.00609 AC: 233 AN: 38248

South Asian (SAS) AF: 0.000184 AC: 15 AN: 81560

European-Finnish (FIN) AF: 0.000123 AC: 6 AN: 48902

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5544

European-Non Finnish (NFE) AF: 0.000178 AC: 191 AN: 1071276

Other (OTH) AF: 0.000224 AC: 13 AN: 58030

GnomAD4 genome AF: 0.000295 AC: 42 AN: 142178 Hom.: 0 Cov.: 31 AF XY: 0.000274 AC XY: 19 AN XY: 69290

African (AFR) AF: 0.0000788 AC: 3 AN: 38058

American (AMR) AF: 0.000619 AC: 9 AN: 14528

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 4 AN: 3284

East Asian (EAS) AF: 0.00222 AC: 11 AN: 4962

South Asian (SAS) AF: 0.00 AC: 0 AN: 4578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000233 AC: 15 AN: 64430

Other (OTH) AF: 0.00 AC: 0 AN: 1962

Alfa AF: 0.000293 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	3	1	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	1	Lynch syndrome 5 (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	MSH6-related disorder (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.0
DANN	Benign	0.81
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0094
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.090		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: rs545466048; hg19: chr2-48033908; COSMIC: COSV52275389; COSMIC: COSV52275389;