Genetic Variant NM_002911.4:c.140C>A (chr19-18832349-C-A) – 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.140C>A(p.Pro47His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000822 in 1,217,250 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. 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. P47L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

UPF1
NM_002911.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.52

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:

Genome browser will be placed here

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=0.27113527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4 link	c.140C>A	p.Pro47His	missense_variant	Exon 1 of 24	ENST00000262803.10	NP_002902.2	Q92900-2A0A024R7L5
UPF1	NM_001297549.2 link	c.140C>A	p.Pro47His	missense_variant	Exon 1 of 24		NP_001284478.1	Q92900-1A0A024R7L8B3KY55
UPF1	XM_017027105.3 link	c.140C>A	p.Pro47His	missense_variant	Exon 1 of 24		XP_016882594.1
UPF1	XM_017027106.3 link	c.140C>A	p.Pro47His	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.140C>A	p.Pro47His	missense_variant	Exon 1 of 24	1	NM_002911.4	ENSP00000262803.5		Q92900-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.22e-7

AC:

AN:

1217250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

601248

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:

25360

American (AMR)

AF:

0.00

AC:

AN:

30154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18674

East Asian (EAS)

AF:

0.00

AC:

AN:

25082

South Asian (SAS)

AF:

0.00

AC:

AN:

57776

European-Finnish (FIN)

AF:

0.0000251

AC:

AN:

39770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

970348

Other (OTH)

AF:

0.00

AC:

AN:

46042

⚠️ 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: 0.275

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

0.19

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.085

.;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.59

T;T

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.0

L;L

PhyloP100

1.5

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

0.25

N;.

REVEL

Benign

0.26

Sift

Benign

0.034

D;.

Sift4G

Benign

0.55

T;T

Polyphen

0.0

B;B

Vest4

0.25

MutPred

0.13

Loss of glycosylation at P47 (P = 0.018);Loss of glycosylation at P47 (P = 0.018);

MVP

0.26

MPC

1.4

ClinPred

0.38

GERP RS

4.0

PromoterAI

0.0044

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.18

gMVP

0.15

Mutation Taster

=90/10

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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