Variant 4-185400462-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_018359.5(UFSP2):c.1340A>C(p.Lys447Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UFSP2
NM_018359.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.63

Variant links:

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 links:

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

ANKRD37 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UFSP2	NM_018359.5 linkuse as main transcript	c.1340A>C	p.Lys447Thr	missense_variant	12/12	ENST00000264689.11
ANKRD37	XM_017008176.2 linkuse as main transcript	c.*685T>G		3_prime_UTR_variant	4/4
UFSP2	NR_028085.2 linkuse as main transcript	n.1411A>C		non_coding_transcript_exon_variant	12/12
UFSP2	NR_144317.2 linkuse as main transcript	n.1539A>C		non_coding_transcript_exon_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UFSP2	ENST00000264689.11 linkuse as main transcript	c.1340A>C	p.Lys447Thr	missense_variant	12/12	2	NM_018359.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148876

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00144

Gnomad SAS

AF:

0.00111

Gnomad FIN

AF:

0.000699

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000299

Gnomad OTH

AF:

0.000486

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0169

AC:

18292

AN:

1083498

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

8479

AN XY:

551874

show subpopulations

Gnomad4 AFR exome

AF:

0.0141

Gnomad4 AMR exome

AF:

0.000972

Gnomad4 ASJ exome

AF:

0.00745

Gnomad4 EAS exome

AF:

0.00748

Gnomad4 SAS exome

AF:

0.00477

Gnomad4 FIN exome

AF:

0.00601

Gnomad4 NFE exome

AF:

0.0205

Gnomad4 OTH exome

AF:

0.0146

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000315

AC:

AN:

149006

Hom.:

Cov.:

AF XY:

0.000371

AC XY:

AN XY:

72710

show subpopulations

Gnomad4 AFR

AF:

0.000171

Gnomad4 AMR

AF:

0.000133

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00124

Gnomad4 SAS

AF:

0.00111

Gnomad4 FIN

AF:

0.000699

Gnomad4 NFE

AF:

0.000284

Gnomad4 OTH

AF:

0.000481

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.1340A>C (p.K447T) alteration is located in exon 12 (coding exon 12) of the UFSP2 gene. This alteration results from a A to C substitution at nucleotide position 1340, causing the lysine (K) at amino acid position 447 to be replaced by a threonine (T). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.071

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

-0.25

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.73

Loss of methylation at K447 (P = 0.0068);

MVP

0.61

MPC

0.46

ClinPred

1.0

GERP RS

6.0

Varity_R

0.87

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over