Genetic Variant UPF3A:c.208-5C>A (chr13-114282016-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_023011.4(UPF3A):c.208-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UPF3A
NM_023011.4 splice_region, intron

Scores

Splicing: ADA: 0.9963

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0200

Publications

0 publications found

Variant links:

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]

UPF3A links:

ENSG00000289904 (HGNC:):

ENSG00000289904 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UPF3A	NM_023011.4	MANE Select	c.208-5C>A	splice_region intron	N/A	NP_075387.1	Q9H1J1-1
UPF3A	NM_001353645.1		c.-666C>A	5_prime_UTR	Exon 1 of 10	NP_001340574.1	B3KUE7
UPF3A	NM_001353646.1		c.-302C>A	5_prime_UTR	Exon 1 of 8	NP_001340575.1	B3KUE7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UPF3A	ENST00000375299.8	TSL:1 MANE Select	c.208-5C>A	splice_region intron	N/A	ENSP00000364448.3	Q9H1J1-1
UPF3A	ENST00000351487.5	TSL:1	c.208-5C>A	splice_region intron	N/A	ENSP00000329592.5	Q9H1J1-2
UPF3A	ENST00000966313.1		c.208-5C>A	splice_region intron	N/A	ENSP00000636372.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000654

AC:

AN:

152866

AF XY:

0.00

show subpopulations

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:

0.0000170

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1397606

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690266

African (AFR)

AF:

0.00

AC:

AN:

31756

American (AMR)

AF:

0.00

AC:

AN:

36356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25200

East Asian (EAS)

AF:

0.00

AC:

AN:

36148

South Asian (SAS)

AF:

0.00

AC:

AN:

79624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081338

Other (OTH)

AF:

0.00

AC:

AN:

57954

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

0.020

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.78

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.51

Position offset: 2

DS_AL_spliceai

0.38

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over