chr4-185403540-T-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 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 (★★). ClinVar reports functional evidence for this variant: "SCV000598615: 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" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D426G) has been classified as Likely 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: 1 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000598615: 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).; SCV000883179: Well-established functional studies show a deleterious effect (https://www.ncbi.nlm.nih.gov/pubmed/21228277).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-185403540-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4526333.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018359.5. 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
	UFSP2	NM_018359.5	MANE Select	c.1277A>C	p.Asp426Ala	missense	Exon 11 of 12	NP_060829.2	Q9NUQ7
	UFSP2	NR_028085.2		n.1348A>C		non_coding_transcript_exon	Exon 11 of 12
	UFSP2	NR_144317.2		n.1476A>C		non_coding_transcript_exon	Exon 11 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UFSP2	ENST00000264689.11	TSL:2 MANE Select	c.1277A>C	p.Asp426Ala	missense	Exon 11 of 12	ENSP00000264689.6	Q9NUQ7
	UFSP2	ENST00000864570.1		c.1319A>C	p.Asp440Ala	missense	Exon 11 of 12	ENSP00000534629.1
	UFSP2	ENST00000913615.1		c.1274A>C	p.Asp425Ala	missense	Exon 11 of 12	ENSP00000583674.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Spondyloepimetaphyseal dysplasia, di rocco type (2)
1	-	-	Hip dysplasia, Beukes type (1)

Computational scores

Source: dbNSFP v4.9

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
Polyphen		0.99	D
Vest4		0.97
MutPred		0.97		Gain of ubiquitination at K421 (P = 0.115)
MVP		0.84
MPC		0.47
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;