rs1416818508

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-18832367-G-C
• chr19-18832367-G-T

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).

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.158G>C	p.Gly53Ala	missense	Exon 1 of 24	NP_002902.2
	UPF1	NM_001297549.2		c.158G>C	p.Gly53Ala	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.158G>C	p.Gly53Ala	missense	Exon 1 of 24	ENSP00000262803.5	Q92900-2
	UPF1	ENST00000599848.5	TSL:1	c.158G>C	p.Gly53Ala	missense	Exon 1 of 24	ENSP00000470142.1	Q92900-1
	UPF1	ENST00000948400.1		c.158G>C	p.Gly53Ala	missense	Exon 1 of 25	ENSP00000618459.1

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.0	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
Polyphen		0.29	B
Vest4		0.23
MutPred		0.21		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;