2-230010838-G-A

Variant names:

• chr2-230010838-G-A
• rs145410117
• NM_174899.5:c.521G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_174899.5(FBXO36):​c.521G>A​(p.Arg174His) variant causes a missense change. The variant allele was found at a frequency of 0.000179 in 1,613,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: FBXO36 NM_174899.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.88
• Publications: 6 publications found

Genes affected

FBXO36 (HGNC:27020): (F-box protein 36) Members of the F-box protein family, such as FBXO36, 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 (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09695688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO36	NM_174899.5	c.521G>A	p.Arg174His	missense_variant	Exon 4 of 4	ENST00000283946.8	NP_777559.3
FBXO36	XM_005246317.3	c.446G>A	p.Arg149His	missense_variant	Exon 4 of 4		XP_005246374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO36	ENST00000283946.8	c.521G>A	p.Arg174His	missense_variant	Exon 4 of 4	1	NM_174899.5	ENSP00000283946.3
FBXO36	ENST00000373652.7	c.428G>A	p.Arg143His	missense_variant	Exon 5 of 5	1		ENSP00000362756.3
FBXO36	ENST00000409992.1	c.461G>A	p.Arg154His	missense_variant	Exon 4 of 4	5		ENSP00000386673.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000216 AC: 54 AN: 249908 AF XY: 0.000178

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 252 AN: 1461144 Hom.: 0 Cov.: 30 AF XY: 0.000166 AC XY: 121 AN XY: 726846

African (AFR) AF: 0.000120 AC: 4 AN: 33458

American (AMR) AF: 0.000493 AC: 22 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111610

Other (OTH) AF: 0.000133 AC: 8 AN: 60360

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74340

African (AFR) AF: 0.0000724 AC: 3 AN: 41442

American (AMR) AF: 0.000982 AC: 15 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000327

EpiControl AF: 0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.521G>A (p.R174H) alteration is located in exon 4 (coding exon 4) of the FBXO36 gene. This alteration results from a G to A substitution at nucleotide position 521, causing the arginine (R) at amino acid position 174 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.013	.;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.097	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	.;M;.
PhyloP100		3.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.034	D;D;T
Polyphen		0.98	.;D;.
Vest4		0.099
MVP		0.54
MPC		0.23
ClinPred		0.21	T
GERP RS		4.0
Varity_R		0.14
gMVP		0.28
Mutation Taster		=86/14	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: rs145410117; hg19: chr2-230875554; COSMIC: COSV52281136;