chr3-48379548-C-T

Variant names:

• chr3-48379548-C-T
• rs1469158336
• NM_207102.2:c.764C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_207102.2(FBXW12):​c.764C>T​(p.Thr255Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FBXW12 NM_207102.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.132
• Publications: 0 publications found

Genes affected

FBXW12 (HGNC:20729): (F-box and WD repeat domain containing 12) Members of the F-box protein family, such as FBXW12, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603034), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046224058).
• BP6: Variant 3-48379548-C-T is Benign according to our data. Variant chr3-48379548-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3278221.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207102.2. 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
	FBXW12	NM_207102.2	MANE Select	c.764C>T	p.Thr255Ile	missense	Exon 7 of 11	NP_996985.2	Q6X9E4-1
	FBXW12	NM_001159929.1		c.707C>T	p.Thr236Ile	missense	Exon 6 of 10	NP_001153401.1	Q6X9E4-3
	FBXW12	NM_001159927.1		c.554C>T	p.Thr185Ile	missense	Exon 6 of 10	NP_001153399.1	Q6X9E4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW12	ENST00000296438.9	TSL:1 MANE Select	c.764C>T	p.Thr255Ile	missense	Exon 7 of 11	ENSP00000296438.5	Q6X9E4-1
	FBXW12	ENST00000445170.5	TSL:1	c.707C>T	p.Thr236Ile	missense	Exon 6 of 10	ENSP00000406139.1	Q6X9E4-3
	FBXW12	ENST00000415155.5	TSL:1	c.554C>T	p.Thr185Ile	missense	Exon 6 of 10	ENSP00000414683.1	Q6X9E4-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251138 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461660 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111830

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.087
DANN	Benign	0.31
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.63	N
PhyloP100		0.13
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.95	N
REVEL	Benign	0.011
Sift	Benign	1.0	T
Sift4G	Benign	0.36	T
Polyphen		0.0020	B
Vest4		0.075
MutPred		0.35		Gain of sheet (P = 0.0266)
MVP		0.33
MPC		0.11
ClinPred		0.026	T
GERP RS		-1.3
Varity_R		0.021
gMVP		0.070
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1469158336; hg19: chr3-48421038;