19-18832349-C-A

Variant names:

• chr19-18832349-C-A
• rs775288936
• NM_002911.4:c.140C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002911.4(UPF1):​c.140C>A​(p.Pro47His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000822 in 1,217,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P47L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: UPF1 NM_002911.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27113527).

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.140C>A	p.Pro47His	missense	Exon 1 of 24	NP_002902.2
	UPF1	NM_001297549.2		c.140C>A	p.Pro47His	missense	Exon 1 of 24	NP_001284478.1	Q92900-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF1	ENST00000262803.10	TSL:1 MANE Select	c.140C>A	p.Pro47His	missense	Exon 1 of 24	ENSP00000262803.5	Q92900-2
	UPF1	ENST00000599848.5	TSL:1	c.140C>A	p.Pro47His	missense	Exon 1 of 24	ENSP00000470142.1	Q92900-1
	UPF1	ENST00000948400.1		c.140C>A	p.Pro47His	missense	Exon 1 of 25	ENSP00000618459.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.22e-7 AC: 1 AN: 1217250 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 601248

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25360

American (AMR) AF: 0.00 AC: 0 AN: 30154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18674

East Asian (EAS) AF: 0.00 AC: 0 AN: 25082

South Asian (SAS) AF: 0.00 AC: 0 AN: 57776

European-Finnish (FIN) AF: 0.0000251 AC: 1 AN: 39770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 970348

Other (OTH) AF: 0.00 AC: 0 AN: 46042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	0.25	N
REVEL	Benign	0.26
Sift	Benign	0.034	D
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.13		Loss of glycosylation at P47 (P = 0.018)
MVP		0.26
MPC		1.4
ClinPred		0.38	T
GERP RS		4.0
PromoterAI		0.0044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.18
gMVP		0.15
Mutation Taster		=90/10	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: rs775288936; hg19: chr19-18943158;