NM_002911.4:c.232-90G>A

Variant names:

• chr19-18845890-G-A
• rs59045002
• NM_002911.4:c.232-90G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002911.4(UPF1):​c.232-90G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,499,678 control chromosomes in the GnomAD database, including 110,779 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9092 hom., cov: 32)
  • Exomes 𝑓: 0.38 (101687 hom.)
• Consequence: UPF1 NM_002911.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.45
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-18845890-G-A is Benign according to our data. Variant chr19-18845890-G-A is described in ClinVar as [Benign]. Clinvar id is 1263694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4	c.232-90G>A		intron_variant	Intron 1 of 23	ENST00000262803.10	NP_002902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF1	ENST00000262803.10	c.232-90G>A		intron_variant	Intron 1 of 23	1	NM_002911.4	ENSP00000262803.5

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47356 AN: 151918 Hom.: 9082 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.365

GnomAD4 exome AF: 0.381 AC: 513726 AN: 1347642 Hom.: 101687 AF XY: 0.378 AC XY: 250650 AN XY: 663056

African (AFR) AF: 0.0904 AC: 2759 AN: 30530

American (AMR) AF: 0.529 AC: 16799 AN: 31784

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 11249 AN: 20834

East Asian (EAS) AF: 0.214 AC: 8107 AN: 37822

South Asian (SAS) AF: 0.242 AC: 17529 AN: 72578

European-Finnish (FIN) AF: 0.345 AC: 13932 AN: 40388

Middle Eastern (MID) AF: 0.468 AC: 2437 AN: 5202

European-Non Finnish (NFE) AF: 0.399 AC: 420325 AN: 1052482

Other (OTH) AF: 0.368 AC: 20589 AN: 56022

GnomAD4 genome AF: 0.312 AC: 47396 AN: 152036 Hom.: 9092 Cov.: 32 AF XY: 0.310 AC XY: 23049 AN XY: 74312

African (AFR) AF: 0.103 AC: 4288 AN: 41510

American (AMR) AF: 0.476 AC: 7269 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1877 AN: 3468

East Asian (EAS) AF: 0.180 AC: 930 AN: 5174

South Asian (SAS) AF: 0.244 AC: 1175 AN: 4816

European-Finnish (FIN) AF: 0.328 AC: 3466 AN: 10564

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27208 AN: 67934

Other (OTH) AF: 0.361 AC: 761 AN: 2108

Alfa AF: 0.365 Hom.: 2220

Bravo AF: 0.319

Asia WGS AF: 0.214 AC: 744 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 15, 2021

GeneDx

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	-0.87
CADD	Benign	0.030
DANN	Benign	0.35
PhyloP100		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs59045002; hg19: chr19-18956699; COSMIC: COSV53197472; COSMIC: COSV53197472;