4-185403534-T-C

Position:

• chr4-185403534-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_018359.5(UFSP2):​c.1283A>G​(p.His428Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: UFSP2 NM_018359.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.66

Genes affected

UFSP2 (HGNC:25640): (UFM1 specific peptidase 2) This gene encodes a highly conserved cysteine protease. The protein cleaves two C-terminal residues from ubiquitin-fold modifier 1, a ubiquitin-like post-translational modifier protein. Activation of ubiquitin-fold modifier 1 by the encoded protein exposes a C-terminal glycine residue that allows interaction with other proteins and transfer to its target protein. An allelic variant of this gene has been associated with Beukes hip dysplasia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a active_site (size 0) in uniprot entity UFSP2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 4-185403534-T-C is Pathogenic according to our data. Variant chr4-185403534-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 916581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UFSP2	NM_018359.5	c.1283A>G	p.His428Arg	missense_variant	11/12	ENST00000264689.11	NP_060829.2
UFSP2	NR_028085.2	n.1354A>G		non_coding_transcript_exon_variant	11/12
UFSP2	NR_144317.2	n.1482A>G		non_coding_transcript_exon_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UFSP2	ENST00000264689.11	c.1283A>G	p.His428Arg	missense_variant	11/12	2	NM_018359.5	ENSP00000264689	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, di rocco type Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 08, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Pediatrics, Affiliated Hospital of Zunyi Medical College, Zunyi Medical College	Jun 10, 2019	In 2018, Di Rocco, M reported for the first time that a novel heterozygous variant exon 11: c.1277A>C of the UFSP2 gene was the cause to spondyloepimetaphyseal dysplasia mainly manifested as: short stature, anterior vertebral dysplasia, hip dysplasia, flat vertebra, spinal metaphyseal dysplasia, irregular acetabular apex, distal femoral metaphyseal dysplasia, proximal tibial metaphyseal dysplasia, osteoarthritis and so on. We describe a boy with spondyloepimetaphyseal dysplasia due to a novel mutation exon 11: c.1283A>G (leading to p. H428R) of the UFSP2 gene. This is the second report to describe children with SEMDs associated with an UFSP2 variant. However, it is the first to describe a UFSP2 gene mutation exon 11: c.1283A>G (leading to p. H428R). Our findings of a novel heterozygous mutation of UFSP2 gene add to the list of 2 reported heterozygous mutations of UFSP2 which led to hereditary osteopathy. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37214758, 36680403, 33473208, 32755715) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		0.97	D
Vest4		0.92
MutPred		0.98		Gain of phosphorylation at T430 (P = 0.1048);
MVP		0.48
MPC		0.47
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs2095515802; hg19: chr4-186324688;