4-185400428-ATA-GCT

Variant names:

• chr4-185400428-ATA-GCT
• NM_018359.5:c.1372_1374delTATinsAGC
• UFSP2 p.Tyr458Ser

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP3

The NM_018359.5(UFSP2):​c.1372_1374delTATinsAGC​(p.Tyr458Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. Y458C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: UFSP2 NM_018359.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.90
• Publications: 0 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]

ANKRD37 (HGNC:29593): (ankyrin repeat domain 37) Located in cytosol; mitochondrion; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-185400429-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 224821.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1372_1374delTATinsAGC	p.Tyr458Ser	missense	N/A	NP_060829.2	Q9NUQ7
	UFSP2	NR_028085.2		n.1443_1445delTATinsAGC		non_coding_transcript_exon	Exon 12 of 12
	UFSP2	NR_144317.2		n.1571_1573delTATinsAGC		non_coding_transcript_exon	Exon 12 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UFSP2	ENST00000264689.11	TSL:2 MANE Select	c.1372_1374delTATinsAGC	p.Tyr458Ser	missense	N/A	ENSP00000264689.6	Q9NUQ7
	UFSP2	ENST00000864570.1		c.1414_1416delTATinsAGC	p.Tyr472Ser	missense	N/A	ENSP00000534629.1
	UFSP2	ENST00000913615.1		c.1369_1371delTATinsAGC	p.Tyr457Ser	missense	N/A	ENSP00000583674.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-186321582;