19-18832400-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002911.4(UPF1):​c.191G>T​(p.Gly64Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000466 in 859,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000047 ( 0 hom. )

Consequence

UPF1
NM_002911.4 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.69
Variant links:
Genes affected
UPF1 (HGNC:9962): (UPF1 RNA helicase and ATPase) This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein is located only in the cytoplasm. When translation ends, it interacts with the protein that is a functional homolog of yeast Upf2p to trigger mRNA decapping. Use of multiple polyadenylation sites has been noted for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21644884).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
UPF1NM_002911.4 linkc.191G>T p.Gly64Val missense_variant Exon 1 of 24 ENST00000262803.10 NP_002902.2 Q92900-2A0A024R7L5
UPF1NM_001297549.2 linkc.191G>T p.Gly64Val missense_variant Exon 1 of 24 NP_001284478.1 Q92900-1A0A024R7L8B3KY55
UPF1XM_017027105.3 linkc.191G>T p.Gly64Val missense_variant Exon 1 of 24 XP_016882594.1
UPF1XM_017027106.3 linkc.191G>T p.Gly64Val missense_variant Exon 1 of 24 XP_016882595.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UPF1ENST00000262803.10 linkc.191G>T p.Gly64Val missense_variant Exon 1 of 24 1 NM_002911.4 ENSP00000262803.5 Q92900-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000466
AC:
4
AN:
859114
Hom.:
0
Cov.:
30
AF XY:
0.00000251
AC XY:
1
AN XY:
399148
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000598
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000347
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 24, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.191G>T (p.G64V) alteration is located in exon 1 (coding exon 1) of the UPF1 gene. This alteration results from a G to T substitution at nucleotide position 191, causing the glycine (G) at amino acid position 64 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.088
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.084
.;T
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.44
N
LIST_S2
Benign
0.64
T;T
M_CAP
Pathogenic
0.95
D
MetaRNN
Benign
0.22
T;T
MetaSVM
Benign
-0.64
T
MutationAssessor
Benign
0.69
N;N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
0.17
N;.
REVEL
Benign
0.20
Sift
Benign
0.30
T;.
Sift4G
Benign
0.33
T;T
Polyphen
0.061
B;B
Vest4
0.23
MutPred
0.22
Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP
0.38
MPC
1.4
ClinPred
0.22
T
GERP RS
0.23
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.10
gMVP
0.21

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1342113393; hg19: chr19-18943209; API