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

Variant summary

Our verdict is Benign. The variant received -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

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: Benign. The variant received -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 VariationId is 711530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 991 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002911.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF1	NM_002911.4	MANE Select	c.630-10C>T		intron	N/A	NP_002902.2
	UPF1	NM_001297549.2		c.630-10C>T		intron	N/A	NP_001284478.1	Q92900-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UPF1	ENST00000262803.10	TSL:1 MANE Select	c.630-10C>T	intron	N/A	ENSP00000262803.5	Q92900-2
UPF1	ENST00000599848.5	TSL:1	c.630-10C>T	intron	N/A	ENSP00000470142.1	Q92900-1
UPF1	ENST00000948400.1		c.630-10C>T	intron	N/A	ENSP00000618459.1

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

GnomAD2 exomes

AF:

0.00632

AC:

1369

AN:

216590

AF XY:

0.00638

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 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

African (AFR)

AF:

0.00214

AC:

AN:

32308

American (AMR)

AF:

0.00522

AC:

207

AN:

39618

Ashkenazi Jewish (ASJ)

AF:

0.000924

AC:

AN:

23810

East Asian (EAS)

AF:

0.00

AC:

AN:

38526

South Asian (SAS)

AF:

0.000890

AC:

AN:

80864

European-Finnish (FIN)

AF:

0.00392

AC:

196

AN:

50058

Middle Eastern (MID)

AF:

0.00802

AC:

AN:

3990

European-Non Finnish (NFE)

AF:

0.0112

AC:

12139

AN:

1083330

Other (OTH)

AF:

0.00720

AC:

417

AN:

57900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

703

1406

2110

2813

3516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

470

940

1410

1880

2350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00651

AC:

991

AN:

152340

Hom.:

Cov.:

AF XY:

0.00566

AC XY:

422

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

41574

American (AMR)

AF:

0.00921

AC:

141

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00103

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

705

AN:

68026

Other (OTH)

AF:

0.00945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

141

188

235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00720

Hom.:

Bravo

AF:

0.00730

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.9

(source)

DANN

Benign

0.67

PhyloP100

0.94

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over