rs12666989

Positions:

• chr7-100889133-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001015072.4(UFSP1):​c.139C>G​(p.Leu47Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,612,576 control chromosomes in the GnomAD database, including 24,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1707 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22800 hom.)
• Consequence: UFSP1 NM_001015072.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.613

Genes affected

UFSP1 (HGNC:33821): (UFM1 specific peptidase 1 (inactive)) This gene encodes a protein that is similar to other Ufm1-specific proteases. Studies in mouse determined that Ufsp1 releases Ufm1 (ubiquitin-fold modifier 1) from its bound conjugated complexes which also makes it into an active form. Because the human UFSP1 protein is shorter on the N-terminus and lacks a conserved Cys active site, it is predicted to be non-functional.[provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011535585).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UFSP1	NM_001015072.4	c.139C>G	p.Leu47Val	missense_variant	1/1	ENST00000388761.4	NP_001015072.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UFSP1	ENST00000388761.4	c.139C>G	p.Leu47Val	missense_variant	1/1		NM_001015072.4	ENSP00000373413
UFSP1	ENST00000672365.3	c.367C>G	p.Leu123Val	missense_variant	1/1			ENSP00000499910	P1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20303 AN: 152012 Hom.: 1712 Cov.: 33

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.140

GnomAD3 exomes AF: 0.154 AC: 37966 AN: 247086 Hom.: 3311 AF XY: 0.155 AC XY: 20866 AN XY: 134282

Gnomad AFR exome AF: 0.0484

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.0398

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.172 AC: 250663 AN: 1460446 Hom.: 22800 Cov.: 35 AF XY: 0.171 AC XY: 124011 AN XY: 726450

Gnomad4 AFR exome AF: 0.0490

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.0271

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.183

Gnomad4 OTH exome AF: 0.160

GnomAD4 genome AF: 0.133 AC: 20299 AN: 152130 Hom.: 1707 Cov.: 33 AF XY: 0.132 AC XY: 9797 AN XY: 74354

Gnomad4 AFR AF: 0.0516

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.0323

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.209

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.139

Alfa AF: 0.178 Hom.: 897

Bravo AF: 0.123

TwinsUK AF: 0.176 AC: 651

ALSPAC AF: 0.175 AC: 674

ESP6500AA AF: 0.0563 AC: 248

ESP6500EA AF: 0.178 AC: 1532

ExAC AF: 0.153 AC: 18572

Asia WGS AF: 0.0790 AC: 275 AN: 3478

EpiCase AF: 0.178

EpiControl AF: 0.175

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.7
DANN	Benign	0.43
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.023
Sift	Benign	0.68	T
Sift4G	Benign	0.30	T
Polyphen		0.77	P
Vest4		0.065
MPC		0.068
ClinPred		0.028	T
GERP RS		2.5
Varity_R		0.076
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs12666989; hg19: chr7-100486754; COSMIC: COSV53817007; COSMIC: COSV53817007;