rs758924331

Variant names:

• chr19-18846064-G-A
• rs758924331
• NM_002911.4:c.316G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-18846064-G-A
• chr19-18846064-G-C

Variant summary

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

The NM_002911.4(UPF1):​c.316G>A​(p.Glu106Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E106Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UPF1 NM_002911.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.56
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4	c.316G>A	p.Glu106Lys	missense_variant	Exon 2 of 24	ENST00000262803.10	NP_002902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF1	ENST00000262803.10	c.316G>A	p.Glu106Lys	missense_variant	Exon 2 of 24	1	NM_002911.4	ENSP00000262803.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251386 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		9.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.61
Sift	Benign	0.057	T;.
Sift4G	Benign	0.13	T;T
Polyphen		0.72	P;B
Vest4		0.81
MutPred		0.42		Gain of methylation at E106 (P = 0.0058);Gain of methylation at E106 (P = 0.0058);
MVP		0.91
MPC		1.5
ClinPred		0.93	D
GERP RS		5.0
Varity_R		0.56
gMVP		0.62
Mutation Taster		=33/67	disease causing

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: rs758924331; hg19: chr19-18956873;