3-196569049-C-T

Variant names:

• chr3-196569049-C-T
• rs974414837
• NM_001105573.2:c.65C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001105573.2(FBXO45):​c.65C>T​(p.Ala22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000722 in 1,107,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: FBXO45 NM_001105573.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22
• Publications: 1 publications found

Genes affected

FBXO45 (HGNC:29148): (F-box protein 45) Members of the F-box protein family, such as FBXO45, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), 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 (summary by Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Jan 2011]

WDR53 (HGNC:28786): (WD repeat domain 53) This gene encodes a protein containing WD domains. The function of this gene is unknown. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08596909).
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105573.2. 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
	FBXO45	NM_001105573.2	MANE Select	c.65C>T	p.Ala22Val	missense	Exon 1 of 3	NP_001099043.1	P0C2W1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO45	ENST00000311630.7	TSL:1 MANE Select	c.65C>T	p.Ala22Val	missense	Exon 1 of 3	ENSP00000310332.6	P0C2W1
	WDR53	ENST00000893402.1		c.-17+86G>A		intron	N/A	ENSP00000563461.1
	FBXO45	ENST00000440469.1	TSL:2	c.-220+262C>T		intron	N/A	ENSP00000389868.1	C9JLC0

Frequencies

GnomAD3 genomes AF: 0.0000483 AC: 7 AN: 144940 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000339

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: 0.00

Gnomad OTH AF: 0.000998

GnomAD4 exome AF: 0.00000104 AC: 1 AN: 962894 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 456656

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 17474

American (AMR) AF: 0.000228 AC: 1 AN: 4380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8708

East Asian (EAS) AF: 0.00 AC: 0 AN: 13664

South Asian (SAS) AF: 0.00 AC: 0 AN: 18926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 846156

Other (OTH) AF: 0.00 AC: 0 AN: 34578

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000483 AC: 7 AN: 144940 Hom.: 0 Cov.: 32 AF XY: 0.0000425 AC XY: 3 AN XY: 70588

African (AFR) AF: 0.00 AC: 0 AN: 38560

American (AMR) AF: 0.000339 AC: 5 AN: 14732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8968

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66188

Other (OTH) AF: 0.000998 AC: 2 AN: 2004

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.058
Sift	Benign	0.064	T
Sift4G	Uncertain	0.036	D
Polyphen		0.0	B
Vest4		0.20
MutPred		0.29		Gain of sheet (P = 0.0266)
MVP		0.32
MPC		1.1
ClinPred		0.18	T
GERP RS		0.22
PromoterAI		-0.0086	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.067
gMVP		0.10
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs974414837; hg19: chr3-196295920;