rs766973453

Variant names:

• chr19-17215827-T-G
• rs766973453
• NM_018467.4:c.128T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-17215827-T-G
• chr19-17215827-T-A
• chr19-17215827-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018467.4(USE1):​c.128T>G​(p.Leu43Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,640 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: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USE1 NM_018467.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.05
• Publications: 1 publications found

Genes affected

USE1 (HGNC:30882): (unconventional SNARE in the ER 1) Predicted to enable SNAP receptor activity. Predicted to be involved in several processes, including lysosomal transport; protein catabolic process; and retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum. Predicted to act upstream of or within endoplasmic reticulum tubular network organization and regulation of ER to Golgi vesicle-mediated transport. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018467.4. 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
	USE1	NM_018467.4	MANE Select	c.128T>G	p.Leu43Trp	missense	Exon 2 of 8	NP_060937.2	Q9NZ43-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USE1	ENST00000263897.10	TSL:1 MANE Select	c.128T>G	p.Leu43Trp	missense	Exon 2 of 8	ENSP00000263897.4	Q9NZ43-1
	USE1	ENST00000596136.5	TSL:1	c.128T>G	p.Leu43Trp	missense	Exon 2 of 7	ENSP00000473239.1	Q9NZ43-2
	USE1	ENST00000593597.2	TSL:2	c.5T>G	p.Leu2Trp	missense	Exon 1 of 7	ENSP00000470065.2	M0QYT5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242852 AF XY: 0.00000758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458640 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725206

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 85496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110748

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	30
DANN	Benign	0.96
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.71		Gain of MoRF binding (P = 0.0507)
MVP		0.79
MPC		1.4
ClinPred		0.94	D
GERP RS		4.6
PromoterAI		-0.20	Neutral
Varity_R		0.50
gMVP		0.71
Mutation Taster		=46/54	disease causing

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

Other links and lift over

dbSNP: rs766973453; hg19: chr19-17326636;