19-18832400-G-T

Variant names:

• chr19-18832400-G-T
• rs1342113393
• NM_002911.4:c.191G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002911.4(UPF1):​c.191G>T​(p.Gly64Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000466 in 859,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: UPF1 NM_002911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21644884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4	c.191G>T	p.Gly64Val	missense_variant	Exon 1 of 24	ENST00000262803.10	NP_002902.2
UPF1	NM_001297549.2	c.191G>T	p.Gly64Val	missense_variant	Exon 1 of 24		NP_001284478.1
UPF1	XM_017027105.3	c.191G>T	p.Gly64Val	missense_variant	Exon 1 of 24		XP_016882594.1
UPF1	XM_017027106.3	c.191G>T	p.Gly64Val	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.191G>T	p.Gly64Val	missense_variant	Exon 1 of 24	1	NM_002911.4	ENSP00000262803.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000466 AC: 4 AN: 859114 Hom.: 0 Cov.: 30 AF XY: 0.00000251 AC XY: 1 AN XY: 399148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000598

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000347

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191G>T (p.G64V) alteration is located in exon 1 (coding exon 1) of the UPF1 gene. This alteration results from a G to T substitution at nucleotide position 191, causing the glycine (G) at amino acid position 64 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.084	.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.64	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.17	N;.
REVEL	Benign	0.20
Sift	Benign	0.30	T;.
Sift4G	Benign	0.33	T;T
Polyphen		0.061	B;B
Vest4		0.23
MutPred		0.22		Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);
MVP		0.38
MPC		1.4
ClinPred		0.22	T
GERP RS		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.10
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs1342113393; hg19: chr19-18943209;