19-18832273-G-C

Variant names:

• chr19-18832273-G-C
• NM_002911.4:c.64G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002911.4(UPF1):​c.64G>C​(p.Glu22Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: UPF1 NM_002911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40735394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4	c.64G>C	p.Glu22Gln	missense_variant	Exon 1 of 24	ENST00000262803.10	NP_002902.2
UPF1	NM_001297549.2	c.64G>C	p.Glu22Gln	missense_variant	Exon 1 of 24		NP_001284478.1
UPF1	XM_017027105.3	c.64G>C	p.Glu22Gln	missense_variant	Exon 1 of 24		XP_016882594.1
UPF1	XM_017027106.3	c.64G>C	p.Glu22Gln	missense_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.64G>C	p.Glu22Gln	missense_variant	Exon 1 of 24	1	NM_002911.4	ENSP00000262803.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399436 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 696178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.25e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 09, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.82	N;.
REVEL	Uncertain	0.39
Sift	Benign	0.039	D;.
Sift4G	Benign	0.28	T;T
Polyphen		0.87	P;P
Vest4		0.38
MutPred		0.15		Loss of glycosylation at T18 (P = 0.1857);Loss of glycosylation at T18 (P = 0.1857);
MVP		0.86
MPC		1.8
ClinPred		0.80	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-18943082;