chr2-47805173-G-A

Variant names:

• chr2-47805173-G-A
• rs7562048
• NM_000179.3:c.3556+146G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000179.3(MSH6):​c.3556+146G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 636,550 control chromosomes in the GnomAD database, including 97,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24559 hom., cov: 32)
  • Exomes 𝑓: 0.54 (72714 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: -0.0120
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-47805173-G-A is Benign according to our data. Variant chr2-47805173-G-A is described in ClinVar as Benign. ClinVar VariationId is 89410.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.3556+146G>A		intron	N/A	NP_000170.1
	MSH6	NM_001406795.1		c.3652+146G>A		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.3562+146G>A		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.3556+146G>A		intron	N/A	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*2903+146G>A		intron	N/A	ENSP00000405294.1
	MSH6	ENST00000699999.1		n.3786G>A		non_coding_transcript_exon	Exon 6 of 9

Frequencies

GnomAD3 genomes AF: 0.561 AC: 84429 AN: 150498 Hom.: 24554 Cov.: 32

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.615

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.546

GnomAD4 exome AF: 0.535 AC: 260106 AN: 485946 Hom.: 72714 AF XY: 0.540 AC XY: 141656 AN XY: 262462

African (AFR) AF: 0.684 AC: 8728 AN: 12758

American (AMR) AF: 0.539 AC: 12638 AN: 23466

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 10031 AN: 16036

East Asian (EAS) AF: 0.858 AC: 26009 AN: 30300

South Asian (SAS) AF: 0.639 AC: 32520 AN: 50874

European-Finnish (FIN) AF: 0.421 AC: 13518 AN: 32098

Middle Eastern (MID) AF: 0.621 AC: 1471 AN: 2368

European-Non Finnish (NFE) AF: 0.483 AC: 140639 AN: 291314

Other (OTH) AF: 0.544 AC: 14552 AN: 26732

GnomAD4 genome AF: 0.561 AC: 84469 AN: 150604 Hom.: 24559 Cov.: 32 AF XY: 0.564 AC XY: 41512 AN XY: 73574

African (AFR) AF: 0.682 AC: 28098 AN: 41198

American (AMR) AF: 0.530 AC: 8021 AN: 15134

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 2114 AN: 3438

East Asian (EAS) AF: 0.861 AC: 4450 AN: 5170

South Asian (SAS) AF: 0.668 AC: 3205 AN: 4800

European-Finnish (FIN) AF: 0.419 AC: 4256 AN: 10152

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32498 AN: 67420

Other (OTH) AF: 0.546 AC: 1148 AN: 2102

Alfa AF: 0.500 Hom.: 16023

Bravo AF: 0.574

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1%

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.77
PhyloP100		-0.012
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs7562048; hg19: chr2-48032312;