NM_018467.4:c.58A>G

Variant names:

• chr19-17215463-A-G
• rs530342370
• NM_018467.4:c.58A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018467.4(USE1):​c.58A>G​(p.Met20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USE1 NM_018467.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15928265).

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.58A>G	p.Met20Val	missense	Exon 1 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.58A>G	p.Met20Val	missense	Exon 1 of 8	ENSP00000263897.4	Q9NZ43-1
	USE1	ENST00000596136.5	TSL:1	c.58A>G	p.Met20Val	missense	Exon 1 of 7	ENSP00000473239.1	Q9NZ43-2
	USE1	ENST00000595101.5	TSL:2	c.58A>G	p.Met20Val	missense	Exon 1 of 5	ENSP00000472362.1	Q9NZ43-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000582 AC: 1 AN: 171714 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1411952 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 697988

African (AFR) AF: 0.00 AC: 0 AN: 32080

American (AMR) AF: 0.00 AC: 0 AN: 36894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25332

East Asian (EAS) AF: 0.00 AC: 0 AN: 36566

South Asian (SAS) AF: 0.00 AC: 0 AN: 80046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087976

Other (OTH) AF: 0.00 AC: 0 AN: 58584

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152238 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000173 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.0046
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.069
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.026	D
Polyphen		0.52	P
Vest4		0.38
MutPred		0.61		Loss of catalytic residue at M20 (P = 0.0036)
MVP		0.58
MPC		0.58
ClinPred		0.44	T
GERP RS		4.2
PromoterAI		-0.057	Neutral
Varity_R		0.46
gMVP		0.33
Mutation Taster		=76/24	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: rs530342370; hg19: chr19-17326272;