Genetic Variant UPF1:c.630-10C>T (chr19-18850678-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002911.4(UPF1):c.630-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 1,562,744 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0093 ( 65 hom. )

Consequence

UPF1
NM_002911.4 intron

Scores

Splicing: ADA: 0.00005582

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.944

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-18850678-C-T is Benign according to our data. Variant chr19-18850678-C-T is described in ClinVar as [Benign]. Clinvar id is 711530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 991 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4 link	c.630-10C>T		intron_variant	Intron 4 of 23	ENST00000262803.10	NP_002902.2	Q92900-2A0A024R7L5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF1	ENST00000262803.10 link	c.630-10C>T		intron_variant	Intron 4 of 23	1	NM_002911.4	ENSP00000262803.5		Q92900-2

Frequencies

GnomAD3 genomes

AF:

0.00652

AC:

992

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00922

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00955

GnomAD3 exomes

AF:

0.00632

AC:

1369

AN:

216590

Hom.:

AF XY:

0.00638

AC XY:

758

AN XY:

118854

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00481

Gnomad ASJ exome

AF:

0.000262

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000668

Gnomad FIN exome

AF:

0.00299

Gnomad NFE exome

AF:

0.0108

Gnomad OTH exome

AF:

0.00783

GnomAD4 exome

AF:

0.00933

AC:

13154

AN:

1410404

Hom.:

Cov.:

AF XY:

0.00910

AC XY:

6329

AN XY:

695620

show subpopulations

Gnomad4 AFR exome

AF:

0.00214

Gnomad4 AMR exome

AF:

0.00522

Gnomad4 ASJ exome

AF:

0.000924

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000890

Gnomad4 FIN exome

AF:

0.00392

Gnomad4 NFE exome

AF:

0.0112

Gnomad4 OTH exome

AF:

0.00720

GnomAD4 genome

AF:

0.00651

AC:

991

AN:

152340

Hom.:

Cov.:

AF XY:

0.00566

AC XY:

422

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00921

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.0104

Gnomad4 OTH

AF:

0.00945

Alfa

AF:

0.00720

Hom.:

Bravo

AF:

0.00730

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 02, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.9

DANN

Benign

0.67

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

1.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000056

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over