19-18832347-G-A

Variant names:

• chr19-18832347-G-A
• rs80065570
• NM_002911.4:c.138G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002911.4(UPF1):​c.138G>A​(p.Thr46Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 1,380,430 control chromosomes in the GnomAD database, including 928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (86 hom., cov: 32)
  • Exomes 𝑓: 0.034 (842 hom.)
• Consequence: UPF1 NM_002911.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.455
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-18832347-G-A is Benign according to our data. Variant chr19-18832347-G-A is described in ClinVar as [Benign]. Clinvar id is 1268198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.455 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4	c.138G>A	p.Thr46Thr	synonymous_variant	Exon 1 of 24	ENST00000262803.10	NP_002902.2
UPF1	NM_001297549.2	c.138G>A	p.Thr46Thr	synonymous_variant	Exon 1 of 24		NP_001284478.1
UPF1	XM_017027105.3	c.138G>A	p.Thr46Thr	synonymous_variant	Exon 1 of 24		XP_016882594.1
UPF1	XM_017027106.3	c.138G>A	p.Thr46Thr	synonymous_variant	Exon 1 of 24		XP_016882595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF1	ENST00000262803.10	c.138G>A	p.Thr46Thr	synonymous_variant	Exon 1 of 24	1	NM_002911.4	ENSP00000262803.5

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4474 AN: 148810 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0295

Gnomad ASJ AF: 0.0431

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.0459

GnomAD2 exomes AF: 0.0299 AC: 5341 AN: 178574 AF XY: 0.0290

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0427

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.0261

Gnomad NFE exome AF: 0.0335

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0344 AC: 42410 AN: 1231512 Hom.: 842 Cov.: 30 AF XY: 0.0344 AC XY: 20917 AN XY: 608780

African (AFR) AF: 0.0125 AC: 322 AN: 25712

American (AMR) AF: 0.0173 AC: 530 AN: 30706

Ashkenazi Jewish (ASJ) AF: 0.0426 AC: 818 AN: 19214

East Asian (EAS) AF: 0.0769 AC: 2008 AN: 26100

South Asian (SAS) AF: 0.00539 AC: 318 AN: 59000

European-Finnish (FIN) AF: 0.0263 AC: 1077 AN: 40926

Middle Eastern (MID) AF: 0.0283 AC: 120 AN: 4240

European-Non Finnish (NFE) AF: 0.0364 AC: 35605 AN: 978802

Other (OTH) AF: 0.0344 AC: 1612 AN: 46812

GnomAD4 genome AF: 0.0300 AC: 4472 AN: 148918 Hom.: 86 Cov.: 32 AF XY: 0.0303 AC XY: 2203 AN XY: 72708

African (AFR) AF: 0.0130 AC: 533 AN: 41120

American (AMR) AF: 0.0295 AC: 443 AN: 15012

Ashkenazi Jewish (ASJ) AF: 0.0431 AC: 148 AN: 3436

East Asian (EAS) AF: 0.101 AC: 514 AN: 5110

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4822

European-Finnish (FIN) AF: 0.0246 AC: 226 AN: 9182

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0352 AC: 2360 AN: 66968

Other (OTH) AF: 0.0454 AC: 94 AN: 2072

Alfa AF: 0.0306 Hom.: 21

Bravo AF: 0.0314

Asia WGS AF: 0.0300 AC: 100 AN: 3392

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

- -

Aug 28, 2019

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	-0.60
CADD	Benign	14
DANN	Benign	0.93
PhyloP100		-0.46
PromoterAI		-0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
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: rs80065570; hg19: chr19-18943156; COSMIC: COSV53195341; COSMIC: COSV53195341;