4-185408335-C-G

Position:

• chr4-185408335-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018359.5(UFSP2):​c.932G>C​(p.Cys311Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,614,114 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (42 hom.)
• Consequence: UFSP2 NM_018359.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.56

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015509248).
• BP6: Variant 4-185408335-C-G is Benign according to our data. Variant chr4-185408335-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 780512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1936/152258) while in subpopulation AFR AF= 0.0444 (1846/41532). AF 95% confidence interval is 0.0428. There are 37 homozygotes in gnomad4. There are 896 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1936 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UFSP2	NM_018359.5	c.932G>C	p.Cys311Ser	missense_variant	8/12	ENST00000264689.11
UFSP2	NR_028085.2	n.1003G>C		non_coding_transcript_exon_variant	8/12
UFSP2	NR_144317.2	n.1028G>C		non_coding_transcript_exon_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UFSP2	ENST00000264689.11	c.932G>C	p.Cys311Ser	missense_variant	8/12	2	NM_018359.5	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1930 AN: 152140 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00308 AC: 775 AN: 251300 Hom.: 8 AF XY: 0.00221 AC XY: 300 AN XY: 135804

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00146 AC: 2137 AN: 1461856 Hom.: 42 Cov.: 31 AF XY: 0.00130 AC XY: 945 AN XY: 727236

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.00308

GnomAD4 genome AF: 0.0127 AC: 1936 AN: 152258 Hom.: 37 Cov.: 32 AF XY: 0.0120 AC XY: 896 AN XY: 74456

Gnomad4 AFR AF: 0.0444

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.00216 Hom.: 4

Bravo AF: 0.0143

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0393 AC: 173

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00376 AC: 456

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hip dysplasia, Beukes type;C4693799:Spondyloepimetaphyseal dysplasia, di rocco type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.013	D
Polyphen		0.68	P
Vest4		0.86
MutPred		0.83		Gain of disorder (P = 0.0307);
MVP		0.92
MPC		0.27
ClinPred		0.050	T
GERP RS		6.0
Varity_R		0.51
gMVP		0.79

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: rs75415917; hg19: chr4-186329489;