chr19-18832300-T-A

Variant names:

• chr19-18832300-T-A
• NM_002911.4:c.91T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_002911.4(UPF1):​c.91T>A​(p.Ser31Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: UPF1 NM_002911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.33
• Publications: 0 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 3 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity RENT1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31362605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF1	NM_002911.4	c.91T>A	p.Ser31Thr	missense_variant	Exon 1 of 24	ENST00000262803.10	NP_002902.2
UPF1	NM_001297549.2	c.91T>A	p.Ser31Thr	missense_variant	Exon 1 of 24		NP_001284478.1
UPF1	XM_017027105.3	c.91T>A	p.Ser31Thr	missense_variant	Exon 1 of 24		XP_016882594.1
UPF1	XM_017027106.3	c.91T>A	p.Ser31Thr	missense_variant	Exon 1 of 24		XP_016882595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF1	ENST00000262803.10	c.91T>A	p.Ser31Thr	missense_variant	Exon 1 of 24	1	NM_002911.4	ENSP00000262803.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 27, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	0.0079	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.093	.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.66	N;N
PhyloP100		4.3
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-0.46	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.24	T;.
Sift4G	Benign	0.32	T;T
Polyphen		0.31	B;B
Vest4		0.38
MutPred		0.14		Loss of phosphorylation at T28 (P = 0.1286);Loss of phosphorylation at T28 (P = 0.1286);
MVP		0.64
MPC		1.1
ClinPred		0.65	D
GERP RS		3.8
PromoterAI		0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.12
gMVP		0.57
Mutation Taster		=60/40	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

hg19: chr19-18943109;