19-17219683-C-T

Variant names:

• chr19-17219683-C-T
• rs201057224
• NM_018467.4:c.650C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018467.4(USE1):​c.650C>T​(p.Thr217Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000324 in 1,612,280 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. T217R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (4 hom.)
• Consequence: USE1 NM_018467.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40
• Publications: 8 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039890856).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.650C>T	p.Thr217Met	missense	Exon 8 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.650C>T	p.Thr217Met	missense	Exon 8 of 8	ENSP00000263897.4	Q9NZ43-1
	USE1	ENST00000596136.5	TSL:1	c.*34C>T		3_prime_UTR	Exon 7 of 7	ENSP00000473239.1	Q9NZ43-2
	USE1	ENST00000593597.2	TSL:2	c.527C>T	p.Thr176Met	missense	Exon 7 of 7	ENSP00000470065.2	M0QYT5

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000433 AC: 108 AN: 249590 AF XY: 0.000466

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.000896

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000442

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.000324 AC: 473 AN: 1459968 Hom.: 4 Cov.: 31 AF XY: 0.000351 AC XY: 255 AN XY: 725918

African (AFR) AF: 0.000359 AC: 12 AN: 33446

American (AMR) AF: 0.000649 AC: 29 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.0116 AC: 65 AN: 5590

European-Non Finnish (NFE) AF: 0.000218 AC: 242 AN: 1110626

Other (OTH) AF: 0.000730 AC: 44 AN: 60278

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74484

African (AFR) AF: 0.0000241 AC: 1 AN: 41556

American (AMR) AF: 0.00131 AC: 20 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000345 Hom.: 1

Bravo AF: 0.000370

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.060
Sift	Benign	0.18	T
Sift4G	Benign	0.19	T
Polyphen		0.19	B
Vest4		0.12
MVP		0.53
MPC		0.40
ClinPred		0.057	T
GERP RS		3.7
Varity_R		0.019
gMVP		0.26
Mutation Taster		=99/1	polymorphism

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: rs201057224; hg19: chr19-17330492; COSMIC: COSV55728449; COSMIC: COSV55728449;