Genetic Variant UPF1:p.Gly52Cys (chr19-18832363-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002911.4(UPF1):c.154G>T(p.Gly52Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000861 in 1,161,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G52S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

UPF1
NM_002911.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.81

Publications

0 publications found

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]

UPF1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, G2P

UPF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2773704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4 link	c.154G>T	p.Gly52Cys	missense_variant	Exon 1 of 24	ENST00000262803.10	NP_002902.2	Q92900-2A0A024R7L5
UPF1	NM_001297549.2 link	c.154G>T	p.Gly52Cys	missense_variant	Exon 1 of 24		NP_001284478.1	Q92900-1A0A024R7L8B3KY55
UPF1	XM_017027105.3 link	c.154G>T	p.Gly52Cys	missense_variant	Exon 1 of 24		XP_016882594.1
UPF1	XM_017027106.3 link	c.154G>T	p.Gly52Cys	missense_variant	Exon 1 of 24		XP_016882595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF1	ENST00000262803.10 link	c.154G>T	p.Gly52Cys	missense_variant	Exon 1 of 24	1	NM_002911.4	ENSP00000262803.5		Q92900-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.61e-7

AC:

AN:

1161302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

570634

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24088

American (AMR)

AF:

0.00

AC:

AN:

26364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16994

East Asian (EAS)

AF:

0.00

AC:

AN:

22206

South Asian (SAS)

AF:

0.00

AC:

AN:

50394

European-Finnish (FIN)

AF:

0.0000291

AC:

AN:

34420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3414

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

940320

Other (OTH)

AF:

0.00

AC:

AN:

43102

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.56

T;T

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.69

N;N

PhyloP100

3.8

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-0.34

N;.

REVEL

Benign

0.24

Sift

Benign

0.032

D;.

Sift4G

Uncertain

0.050

T;T

Polyphen

0.0

B;B

Vest4

0.23

MutPred

0.25

Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);

MVP

0.62

MPC

1.4

ClinPred

0.49

GERP RS

2.7

PromoterAI

0.062

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.21

gMVP

0.42

Mutation Taster

=90/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over