NM_018467.4:c.568G>T

Variant names:

• chr19-17219358-G-T
• rs767469086
• NM_018467.4:c.568G>T

Variant summary

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

The NM_018467.4(USE1):​c.568G>T​(p.Ala190Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,416,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A190T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USE1 NM_018467.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71
• Publications: 0 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, 0.762

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.568G>T	p.Ala190Ser	missense	Exon 7 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.568G>T	p.Ala190Ser	missense	Exon 7 of 8	ENSP00000263897.4	Q9NZ43-1
	USE1	ENST00000596136.5	TSL:1	c.423-273G>T		intron	N/A	ENSP00000473239.1	Q9NZ43-2
	USE1	ENST00000593597.2	TSL:2	c.445G>T	p.Ala149Ser	missense	Exon 6 of 7	ENSP00000470065.2	M0QYT5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1416568 Hom.: 0 Cov.: 33 AF XY: 0.00000285 AC XY: 2 AN XY: 700828

African (AFR) AF: 0.00 AC: 0 AN: 32074

American (AMR) AF: 0.00 AC: 0 AN: 37152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25354

East Asian (EAS) AF: 0.00 AC: 0 AN: 36810

South Asian (SAS) AF: 0.00 AC: 0 AN: 81186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50722

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1088782

Other (OTH) AF: 0.00 AC: 0 AN: 58770

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.25
Sift	Benign	0.11	T
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.72		Gain of methylation at K195 (P = 0.1006)
MVP		0.65
MPC		1.0
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.55
Mutation Taster		=36/64	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: rs767469086; hg19: chr19-17330167; COSMIC: COSV99812357; COSMIC: COSV99812357;