chr13-114282104-C-A

Variant names:

• chr13-114282104-C-A
• rs1210533634
• NM_023011.4:c.291C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_023011.4(UPF3A):​c.291C>A​(p.Phe97Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000422 in 1,420,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: UPF3A NM_023011.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.788
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

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.291C>A	p.Phe97Leu	missense	Exon 2 of 10	NP_075387.1	Q9H1J1-1
	UPF3A	NM_080687.3		c.291C>A	p.Phe97Leu	missense	Exon 2 of 9	NP_542418.1	Q9H1J1-2
	UPF3A	NM_001353651.2		c.291C>A	p.Phe97Leu	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.291C>A	p.Phe97Leu	missense	Exon 2 of 10	ENSP00000364448.3	Q9H1J1-1
	UPF3A	ENST00000351487.5	TSL:1	c.291C>A	p.Phe97Leu	missense	Exon 2 of 9	ENSP00000329592.5	Q9H1J1-2
	UPF3A	ENST00000966313.1		c.291C>A	p.Phe97Leu	missense	Exon 2 of 11	ENSP00000636372.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000120 AC: 2 AN: 166138 AF XY: 0.0000220

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: 0.0000152

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1420952 Hom.: 0 Cov.: 33 AF XY: 0.00000427 AC XY: 3 AN XY: 703330

African (AFR) AF: 0.00 AC: 0 AN: 32530

American (AMR) AF: 0.00 AC: 0 AN: 39206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25474

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37498

South Asian (SAS) AF: 0.00 AC: 0 AN: 81310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000458 AC: 5 AN: 1092394

Other (OTH) AF: 0.00 AC: 0 AN: 58866

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.035
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.79
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.55
Sift	Benign	0.12	T
Sift4G	Benign	0.25	T
Polyphen		0.99	D
Vest4		0.91
MutPred		0.75		Loss of sheet (P = 0.0457)
MVP		0.87
MPC		0.75
ClinPred		0.99	D
GERP RS		0.070
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.54
Mutation Taster		=42/58	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: rs1210533634; hg19: chr13-115047579;