chr13-114282078-C-T

Variant names:

• chr13-114282078-C-T
• rs761474818
• NM_023011.4:c.265C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023011.4(UPF3A):​c.265C>T​(p.Arg89Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000049 in 1,427,784 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: 0.0000049 (0 hom.)
• Consequence: UPF3A NM_023011.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76
• Publications: 0 publications found

Genes affected

UPF3A (HGNC:20332): (UPF3A regulator of nonsense mediated mRNA decay) This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. The encoded protein is one of two functional homologs to yeast Upf3p. 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 binds to the mRNA and remains bound after nuclear export, acting as a nucleocytoplasmic shuttling protein. It forms with Y14 a complex that binds specifically 20 nt upstream of exon-exon junctions. This gene is located on the long arm of chromosome 13. Several splice variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

ENSG00000289904 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38789243).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023011.4. 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
	UPF3A	NM_023011.4	MANE Select	c.265C>T	p.Arg89Cys	missense	Exon 2 of 10	NP_075387.1	Q9H1J1-1
	UPF3A	NM_080687.3		c.265C>T	p.Arg89Cys	missense	Exon 2 of 9	NP_542418.1	Q9H1J1-2
	UPF3A	NM_001353651.2		c.265C>T	p.Arg89Cys	missense	Exon 2 of 5	NP_001340580.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF3A	ENST00000375299.8	TSL:1 MANE Select	c.265C>T	p.Arg89Cys	missense	Exon 2 of 10	ENSP00000364448.3	Q9H1J1-1
	UPF3A	ENST00000351487.5	TSL:1	c.265C>T	p.Arg89Cys	missense	Exon 2 of 9	ENSP00000329592.5	Q9H1J1-2
	UPF3A	ENST00000966313.1		c.265C>T	p.Arg89Cys	missense	Exon 2 of 11	ENSP00000636372.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000558 AC: 1 AN: 179304 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000350

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: 0.00

GnomAD4 exome AF: 0.00000490 AC: 7 AN: 1427784 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 707394

African (AFR) AF: 0.00 AC: 0 AN: 32738

American (AMR) AF: 0.0000248 AC: 1 AN: 40300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25550

East Asian (EAS) AF: 0.00 AC: 0 AN: 37914

South Asian (SAS) AF: 0.00 AC: 0 AN: 82002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00000547 AC: 6 AN: 1096178

Other (OTH) AF: 0.00 AC: 0 AN: 59070

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000861 AC: 1

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	0.091
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.8
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.044	D
Polyphen		0.96	D
Vest4		0.19
MutPred		0.62		Loss of disorder (P = 0.0231)
MVP		0.68
MPC		0.24
ClinPred		0.98	D
GERP RS		4.8
PromoterAI		-0.020	Neutral
Varity_R		0.37
gMVP		0.31
Mutation Taster		=89/11	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: rs761474818; hg19: chr13-115047553;