rs1247771832

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002911.4(UPF1):c.188G>A(p.Gly63Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000678 in 147,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UPF1
NM_002911.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.18958575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4 link	c.188G>A	p.Gly63Asp	missense_variant	Exon 1 of 24	ENST00000262803.10	NP_002902.2	Q92900-2A0A024R7L5
UPF1	NM_001297549.2 link	c.188G>A	p.Gly63Asp	missense_variant	Exon 1 of 24		NP_001284478.1	Q92900-1A0A024R7L8B3KY55
UPF1	XM_017027105.3 link	c.188G>A	p.Gly63Asp	missense_variant	Exon 1 of 24		XP_016882594.1
UPF1	XM_017027106.3 link	c.188G>A	p.Gly63Asp	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.188G>A	p.Gly63Asp	missense_variant	Exon 1 of 24	1	NM_002911.4	ENSP00000262803.5		Q92900-2

Frequencies

GnomAD3 genomes

AF:

0.00000678

AC:

AN:

147596

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

881804

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

411106

African (AFR)

AF:

0.00

AC:

AN:

16802

American (AMR)

AF:

0.00

AC:

AN:

2300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6530

East Asian (EAS)

AF:

0.00

AC:

AN:

6962

South Asian (SAS)

AF:

0.00

AC:

AN:

17696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1846

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

792808

Other (OTH)

AF:

0.00

AC:

AN:

30116

GnomAD4 genome

AF:

0.00000678

AC:

AN:

147596

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40898

American (AMR)

AF:

0.00

AC:

AN:

14834

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

5130

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66388

Other (OTH)

AF:

0.00

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.188G>A (p.G63D) alteration is located in exon 1 (coding exon 1) of the UPF1 gene. This alteration results from a G to A substitution at nucleotide position 188, causing the glycine (G) at amino acid position 63 to be replaced by an aspartic acid (D). 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

0.25

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.079

.;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.67

T;T

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.0

N;N

PhyloP100

2.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.21

N;.

REVEL

Uncertain

0.30

Sift

Benign

0.68

T;.

Sift4G

Benign

0.69

T;T

Polyphen

0.0

B;B

Vest4

0.24

MutPred

0.20

Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);

MVP

0.52

MPC

1.5

ClinPred

0.093

GERP RS

1.9

PromoterAI

0.0018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.071

gMVP

0.23

Mutation Taster

=89/11

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over