19-18832367-G-C

Variant names:

• chr19-18832367-G-C
• rs1416818508
• NM_002911.4:c.158G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002911.4(UPF1):​c.158G>C​(p.Gly53Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000383 in 1,306,996 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: UPF1 NM_002911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2287991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4	c.158G>C	p.Gly53Ala	missense_variant	Exon 1 of 24	ENST00000262803.10	NP_002902.2
UPF1	NM_001297549.2	c.158G>C	p.Gly53Ala	missense_variant	Exon 1 of 24		NP_001284478.1
UPF1	XM_017027105.3	c.158G>C	p.Gly53Ala	missense_variant	Exon 1 of 24		XP_016882594.1
UPF1	XM_017027106.3	c.158G>C	p.Gly53Ala	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.158G>C	p.Gly53Ala	missense_variant	Exon 1 of 24	1	NM_002911.4	ENSP00000262803.5

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 147844 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000259 AC: 3 AN: 1159152 Hom.: 0 Cov.: 30 AF XY: 0.00000176 AC XY: 1 AN XY: 569464

African (AFR) AF: 0.00 AC: 0 AN: 24016

American (AMR) AF: 0.00 AC: 0 AN: 26210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16960

East Asian (EAS) AF: 0.00 AC: 0 AN: 22106

South Asian (SAS) AF: 0.00 AC: 0 AN: 50182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3378

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 939030

Other (OTH) AF: 0.0000465 AC: 2 AN: 43020

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 147844 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 72016

African (AFR) AF: 0.00 AC: 0 AN: 40906

American (AMR) AF: 0.000135 AC: 2 AN: 14858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66578

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.158G>C (p.G53A) alteration is located in exon 1 (coding exon 1) of the UPF1 gene. This alteration results from a G to C substitution at nucleotide position 158, causing the glycine (G) at amino acid position 53 to be replaced by an alanine (A). 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	0.087
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.75
DEOGEN2	Benign	0.078	.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.55	T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		2.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	0.29	N;.
REVEL	Benign	0.23
Sift	Benign	0.80	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.29	B;B
Vest4		0.23
MutPred		0.21		Loss of glycosylation at P54 (P = 0.1971);Loss of glycosylation at P54 (P = 0.1971);
MVP		0.50
MPC		1.3
ClinPred		0.22	T
GERP RS		3.8
PromoterAI		-0.063	Neutral
Varity_R		0.12
gMVP		0.21
Mutation Taster		=96/4	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: rs1416818508; hg19: chr19-18943176;