16-30928546-C-G

Variant names:

• chr16-30928546-C-G
• rs202132610
• NM_001382779.1:c.707C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382779.1(FBXL19):​c.707C>G​(p.Pro236Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,708 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P236L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FBXL19 NM_001382779.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.511
• Publications: 4 publications found

Genes affected

FBXL19 (HGNC:25300): (F-box and leucine rich repeat protein 19) This gene encodes a member of the Skp1-Cullin-F-box family of E3 ubiquitin ligases. The encoded protein is reported to bind to the transmembrane receptor interleukin 1 receptor-like 1 and regulate its ubiquitination and degradation. This protein has been linked to the regulation of pulmonary inflammation and psoriasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116342485).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382779.1. 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
	FBXL19	NM_001382779.1	MANE Select	c.707C>G	p.Pro236Arg	missense	Exon 6 of 11	NP_001369708.1	H3BPZ0
	FBXL19	NM_001099784.3		c.767C>G	p.Pro256Arg	missense	Exon 6 of 11	NP_001093254.2	Q6PCT2-1
	FBXL19	NM_001282351.1		c.-172C>G		5_prime_UTR	Exon 6 of 11	NP_001269280.1	H3BVB1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL19	ENST00000338343.10	TSL:5 MANE Select	c.707C>G	p.Pro236Arg	missense	Exon 6 of 11	ENSP00000339712.4	H3BPZ0
	FBXL19	ENST00000427128.5	TSL:1	c.522+47C>G		intron	N/A	ENSP00000397913.1	H7C112
	FBXL19	ENST00000562319.7	TSL:2	c.767C>G	p.Pro256Arg	missense	Exon 6 of 11	ENSP00000455529.2	Q6PCT2-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455708 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723944

⚠️ 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: 33098

American (AMR) AF: 0.0000226 AC: 1 AN: 44160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 38916

South Asian (SAS) AF: 0.00 AC: 0 AN: 85456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109258

Other (OTH) AF: 0.00 AC: 0 AN: 60074

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00109982), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.51
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.084
Sift	Benign	0.039	D
Sift4G	Benign	0.11	T
Polyphen		0.69	P
Vest4		0.39
MutPred		0.21		Gain of methylation at P256 (P = 0.0188)
MVP		0.043
MPC		0.022
ClinPred		0.21	T
GERP RS		5.0
Varity_R		0.096
gMVP		0.52
Mutation Taster		=285/15	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: rs202132610; hg19: chr16-30939867;