19-17219383-A-T

Variant names:

• chr19-17219383-A-T
• rs1232843737
• NM_018467.4:c.593A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018467.4(USE1):​c.593A>T​(p.Asn198Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,204 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: USE1 NM_018467.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.20

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USE1	NM_018467.4	c.593A>T	p.Asn198Ile	missense_variant	Exon 7 of 8	ENST00000263897.10	NP_060937.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USE1	ENST00000263897.10	c.593A>T	p.Asn198Ile	missense_variant	Exon 7 of 8	1	NM_018467.4	ENSP00000263897.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.6	D;.;.
REVEL	Uncertain	0.38
Sift	Benign	0.15	T;.;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.96	D;.;.
Vest4		0.85
MutPred		0.55		Loss of ubiquitination at K196 (P = 0.0596);.;.;
MVP		0.64
MPC		0.67
ClinPred		0.95	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.49
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1232843737; hg19: chr19-17330192;