rs1556384218

Variant names:

• chrX-119852808-C-T
• rs1556384218
• NM_080632.3:c.121G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000276201.7(UPF3B):​c.121G>A​(p.Asp41Asn) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: UPF3B ENST00000276201.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45
• Publications: 0 publications found

Genes affected

UPF3B (HGNC:20439): (UPF3B 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 X. Two splice variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

UPF3B Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability 14

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19431531).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000276201.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF3B	NM_080632.3	MANE Select	c.121G>A	p.Asp41Asn	missense	Exon 1 of 11	NP_542199.1
	UPF3B	NM_023010.4		c.121G>A	p.Asp41Asn	missense	Exon 1 of 10	NP_075386.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF3B	ENST00000276201.7	TSL:1 MANE Select	c.121G>A	p.Asp41Asn	missense	Exon 1 of 11	ENSP00000276201.3
	UPF3B	ENST00000345865.6	TSL:1	c.121G>A	p.Asp41Asn	missense	Exon 1 of 10	ENSP00000245418.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

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	0.28
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.052	T
Polyphen		0.94	P
Vest4		0.19
MutPred		0.15		Gain of MoRF binding (P = 0.0321)
MVP		0.58
MPC		0.86
ClinPred		0.69	D
GERP RS		3.0
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.079
Mutation Taster		=91/9	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: rs1556384218; hg19: chrX-118986771;