NM_080632.3:c.1121G>A

Variant names:

• chrX-119837938-C-T
• rs143538947
• NM_080632.3:c.1121G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_080632.3(UPF3B):​c.1121G>A​(p.Arg374His) variant causes a missense change. The variant allele was found at a frequency of 0.000539 in 1,208,797 control chromosomes in the GnomAD database, including 2 homozygotes. There are 179 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R374C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., 43 hem., cov: 22)
  • Exomes 𝑓: 0.00043 (1 hom. 136 hem.)
• Consequence: UPF3B NM_080632.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 5.54
• Publications: 6 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009404898).
• BP6: Variant X-119837938-C-T is Benign according to our data. Variant chrX-119837938-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212546.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00159 (177/111215) while in subpopulation AFR AF = 0.00513 (157/30587). AF 95% confidence interval is 0.00448. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 43 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080632.3. 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
	UPF3B	NM_080632.3	MANE Select	c.1121G>A	p.Arg374His	missense	Exon 10 of 11	NP_542199.1	Q9BZI7-1
	UPF3B	NM_023010.4		c.1082G>A	p.Arg361His	missense	Exon 9 of 10	NP_075386.1	Q9BZI7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UPF3B	ENST00000276201.7	TSL:1 MANE Select	c.1121G>A	p.Arg374His	missense	Exon 10 of 11	ENSP00000276201.3	Q9BZI7-1
	UPF3B	ENST00000345865.6	TSL:1	c.1082G>A	p.Arg361His	missense	Exon 9 of 10	ENSP00000245418.2	Q9BZI7-2
	UPF3B	ENST00000951330.1		c.1199G>A	p.Arg400His	missense	Exon 10 of 11	ENSP00000621389.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 177 AN: 111160 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000872

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000381

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00202

GnomAD2 exomes AF: 0.000521 AC: 95 AN: 182342 AF XY: 0.000418

Gnomad AFR exome AF: 0.00593

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000433 AC: 475 AN: 1097582 Hom.: 1 Cov.: 31 AF XY: 0.000375 AC XY: 136 AN XY: 363042

African (AFR) AF: 0.00763 AC: 201 AN: 26355

American (AMR) AF: 0.000171 AC: 6 AN: 35163

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000925 AC: 5 AN: 54040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40166

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4136

European-Non Finnish (NFE) AF: 0.000277 AC: 233 AN: 842060

Other (OTH) AF: 0.000608 AC: 28 AN: 46076

GnomAD4 genome AF: 0.00159 AC: 177 AN: 111215 Hom.: 1 Cov.: 22 AF XY: 0.00129 AC XY: 43 AN XY: 33421

African (AFR) AF: 0.00513 AC: 157 AN: 30587

American (AMR) AF: 0.000870 AC: 9 AN: 10339

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.000382 AC: 1 AN: 2619

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53116

Other (OTH) AF: 0.00199 AC: 3 AN: 1507

Alfa AF: 0.000629 Hom.: 31

Bravo AF: 0.00195

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00574 AC: 22

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000568 AC: 69

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Syndromic X-linked intellectual disability 14 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.14
MVP		0.92
MPC		1.4
ClinPred		0.052	T
GERP RS		5.0
PromoterAI		0.0030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.042
Mutation Taster		=95/5	polymorphism (auto)

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: rs143538947; hg19: chrX-118971901; COSMIC: COSV52230894; COSMIC: COSV52230894;