Variant 10-11931735-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015542.4(UPF2):c.3594C>G(p.His1198Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

UPF2
NM_015542.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.108

Variant links:

Genes affected

UPF2 (HGNC:17854): (UPF2 regulator of nonsense mediated mRNA decay) 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 in the perinuclear area. It interacts with translation release factors and the proteins that are functional homologs of yeast Upf1p and Upf3p. Two splice variants have been found for this gene; both variants encode the same protein. [provided by RefSeq, Jul 2008]

UPF2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UPF2	NM_015542.4 linkuse as main transcript	c.3594C>G	p.His1198Gln	missense_variant	20/22	ENST00000357604.10
UPF2	NM_080599.3 linkuse as main transcript	c.3594C>G	p.His1198Gln	missense_variant	20/22
UPF2	XM_047424986.1 linkuse as main transcript	c.3594C>G	p.His1198Gln	missense_variant	20/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
UPF2	ENST00000357604.10 linkuse as main transcript	c.3594C>G	p.His1198Gln	missense_variant	20/22	1	NM_015542.4	P1
UPF2	ENST00000356352.6 linkuse as main transcript	c.3594C>G	p.His1198Gln	missense_variant	19/21	1		P1
UPF2	ENST00000397053.6 linkuse as main transcript	c.3594C>G	p.His1198Gln	missense_variant	20/22	5		P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461398

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2023

The c.3594C>G (p.H1198Q) alteration is located in exon 20 (coding exon 19) of the UPF2 gene. This alteration results from a C to G substitution at nucleotide position 3594, causing the histidine (H) at amino acid position 1198 to be replaced by a glutamine (Q). 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

Pathogenic

0.72

BayesDel_addAF

Benign

0.0037

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.058

T;T;T

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.90

.;.;D

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.4

L;L;L

MutationTaster

Benign

0.96

D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.98

N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.034

D;D;D

Sift4G

Uncertain

0.019

D;D;D

Polyphen

0.97

D;D;D

Vest4

0.62

MutPred

0.67

Gain of disorder (P = 0.0827);Gain of disorder (P = 0.0827);Gain of disorder (P = 0.0827);

MVP

0.68

MPC

1.4

ClinPred

0.71

GERP RS

-6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over