4-185403540-T-G

Variant names:

• chr4-185403540-T-G
• rs1554022725
• NM_018359.5:c.1277A>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_018359.5(UFSP2):​c.1277A>C​(p.Asp426Ala) 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. Variant has been reported in ClinVar as Pathogenic (★★).

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

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]

UFSP2 Gene-Disease associations (from GenCC):

• hip dysplasia, Beukes type

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• developmental and epileptic encephalopathy 106

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 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, 0.99
• PP5: Variant 4-185403540-T-G is Pathogenic according to our data. Variant chr4-185403540-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 437868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UFSP2	NM_018359.5	c.1277A>C	p.Asp426Ala	missense_variant	Exon 11 of 12	ENST00000264689.11	NP_060829.2
UFSP2	NR_028085.2	n.1348A>C		non_coding_transcript_exon_variant	Exon 11 of 12
UFSP2	NR_144317.2	n.1476A>C		non_coding_transcript_exon_variant	Exon 11 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UFSP2	ENST00000264689.11	c.1277A>C	p.Asp426Ala	missense_variant	Exon 11 of 12	2	NM_018359.5	ENSP00000264689.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, di rocco type Pathogenic:2

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Pathogenic, for Spondyloepimetaphyseal dysplasia, Di Rocco type, autosomal dominant. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/28892125). PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. PS3 => Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/21228277).

Sep 01, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Hip dysplasia, Beukes type Pathogenic:1

UOSD Genetics and Genomics of Rare Diseases, Istituto Giannina Gaslini

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Exome Sequencing allowed us to identify the heterozygous variant c.1277A>C (p.D426A) of the UFSP2 gene in all the affected members of a family with recurrence of Beukes Hip Dysplasia. This mutation is predicted as damaging by numerous softwares (Polyphen-2, SIFT, Mutation Taster2, etc), with a CADD score >20. In addition, based on in vitro mutagenesis already reported, the mutation directly affects one of the catalytic residues participating in the active site of the protein (Ha BH, Jeon YJ, Shin SC, et al. Structure of ubiquitin-fold modifier 1-specific protease UfSP2. J Biol Chem 2011; 286:10248-57).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Vest4		0.97
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.86
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs1554022725; hg19: chr4-186324694;