rs34625968

Variant names:

• chr2-47806561-G-A
• rs34625968
• NM_000179.3:c.3911G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47806561-G-A
• chr2-47806561-G-C
• chr2-47806561-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS1

The NM_000179.3(MSH6):​c.3911G>A​(p.Arg1304Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000412 in 1,613,752 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1304M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:13
• Conservation: PhyloP100: 5.88
• 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 -14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 60 uncertain in NM_000179.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.015989631).
• BP6: Variant 2-47806561-G-A is Benign according to our data. Variant chr2-47806561-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 89479.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0023 (350/152124) while in subpopulation AFR AF = 0.00805 (334/41502). AF 95% confidence interval is 0.00734. There are 1 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3911G>A	p.Arg1304Lys	missense	Exon 9 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4007G>A	p.Arg1336Lys	missense	Exon 10 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.3917G>A	p.Arg1306Lys	missense	Exon 9 of 10	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.3911G>A	p.Arg1304Lys	missense	Exon 9 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3258G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000445503.5	TSL:1	n.*3258G>A		3_prime_UTR	Exon 8 of 9	ENSP00000405294.1	F8WAX8

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 349 AN: 152006 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00805

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000535 AC: 134 AN: 250468 AF XY: 0.000391

Gnomad AFR exome AF: 0.00727

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.000216 AC: 315 AN: 1461628 Hom.: 1 Cov.: 35 AF XY: 0.000160 AC XY: 116 AN XY: 727120

African (AFR) AF: 0.00804 AC: 269 AN: 33472

American (AMR) AF: 0.000335 AC: 15 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111886

Other (OTH) AF: 0.000414 AC: 25 AN: 60386

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152124 Hom.: 1 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74372

African (AFR) AF: 0.00805 AC: 334 AN: 41502

American (AMR) AF: 0.000590 AC: 9 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67986

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000641 Hom.: 2

Bravo AF: 0.00263

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000774 AC: 94

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	1	3	not specified (4)
-	-	2	Lynch syndrome 5 (2)
-	1	1	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.26	N
PhyloP100		5.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.44
Sift	Benign	0.26	T
Sift4G	Benign	0.47	T
Polyphen		0.70	P
Vest4		0.47
MVP		0.81
ClinPred		0.046	T
GERP RS		3.2
Varity_R		0.24
gMVP		0.67
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34625968; hg19: chr2-48033700;