19-18845988-C-T

Variant names:

• chr19-18845988-C-T
• rs35427308
• NM_002911.4:c.240C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002911.4(UPF1):​c.240C>T​(p.Pro80Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,613,934 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (11 hom.)
• Consequence: UPF1 NM_002911.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.93
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-18845988-C-T is Benign according to our data. Variant chr19-18845988-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2649593.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BS2: High AC in GnomAd4 at 407 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4	c.240C>T	p.Pro80Pro	synonymous_variant	Exon 2 of 24	ENST00000262803.10	NP_002902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF1	ENST00000262803.10	c.240C>T	p.Pro80Pro	synonymous_variant	Exon 2 of 24	1	NM_002911.4	ENSP00000262803.5

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 407 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00243 AC: 609 AN: 250650 AF XY: 0.00235

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00411

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00309 AC: 4513 AN: 1461636 Hom.: 11 Cov.: 31 AF XY: 0.00303 AC XY: 2205 AN XY: 727128

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00143 AC: 64 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86252

European-Finnish (FIN) AF: 0.00434 AC: 231 AN: 53226

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.00353 AC: 3925 AN: 1111968

Other (OTH) AF: 0.00230 AC: 139 AN: 60390

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00244 AC XY: 182 AN XY: 74464

African (AFR) AF: 0.000529 AC: 22 AN: 41554

American (AMR) AF: 0.00275 AC: 42 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00329 AC: 35 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00410 AC: 279 AN: 68018

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00350 Hom.: 2

Bravo AF: 0.00254

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

UPF1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.5
DANN	Benign	0.61
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=97/3	polymorphism

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: rs35427308; hg19: chr19-18956797;