7-100889216-T-A

Variant names:

• chr7-100889216-T-A
• rs746962787
• NM_001015072.4:c.56A>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001015072.4(UFSP1):​c.56A>T​(p.Glu19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,440,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: UFSP1 NM_001015072.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UFSP1	NM_001015072.4	c.56A>T	p.Glu19Val	missense_variant	Exon 1 of 1	ENST00000388761.4	NP_001015072.2
UFSP1	NM_001430944.2	c.284A>T	p.Glu95Val	missense_variant	Exon 1 of 1		NP_001417873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UFSP1	ENST00000388761.4	c.56A>T	p.Glu19Val	missense_variant	Exon 1 of 1	6	NM_001015072.4	ENSP00000373413.2
UFSP1	ENST00000672365.3	c.284A>T	p.Glu95Val	missense_variant	Exon 1 of 1			ENSP00000499910.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.000115 AC: 25 AN: 216660 Hom.: 0 AF XY: 0.000142 AC XY: 17 AN XY: 119864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000774

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000174 AC: 25 AN: 1440924 Hom.: 0 Cov.: 33 AF XY: 0.0000196 AC XY: 14 AN XY: 715292

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000555

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000453

ExAC AF: 0.0000845 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56A>T (p.E19V) alteration is located in exon 1 (coding exon 1) of the UFSP1 gene. This alteration results from a A to T substitution at nucleotide position 56, causing the glutamic acid (E) at amino acid position 19 to be replaced by a valine (V). 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	0.93
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.014	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.87		Gain of stability (P = 0.1273);
MVP		0.61
MPC		0.42
ClinPred		0.90	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746962787; hg19: chr7-100486837;