X-119837615-C-CAA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_080632.3(UPF3B):c.1302+141_1302+142insTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 395,480 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., 10 hem., cov: 16)
  • Exomes 𝑓: 0.0060 (0 hom. 0 hem.)
• Consequence: UPF3B NM_080632.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.74

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant X-119837615-C-CAA is Benign according to our data. Variant chrX-119837615-C-CAA is described in ClinVar as [Likely_benign]. Clinvar id is 1188326.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0028 (124/44275) while in subpopulation AFR AF= 0.00809 (118/14591). AF 95% confidence interval is 0.0069. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 16. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPF3B	NM_080632.3	c.1302+141_1302+142insTT		intron_variant		ENST00000276201.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPF3B	ENST00000276201.7	c.1302+141_1302+142insTT		intron_variant		1	NM_080632.3	A1
UPF3B	ENST00000345865.6	c.1263+141_1263+142insTT		intron_variant		1		P4

Frequencies

GnomAD3 genomes AF: 0.00280 AC: 124 AN: 44265 Hom.: 0 Cov.: 16 AF XY: 0.00135 AC XY: 10 AN XY: 7385

Gnomad AFR AF: 0.00810

Gnomad AMI AF: 0.00418

Gnomad AMR AF: 0.000585

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000845

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000879

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000471

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00603 AC: 2118 AN: 351205 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 104067

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.00645

Gnomad4 ASJ exome AF: 0.00726

Gnomad4 EAS exome AF: 0.00496

Gnomad4 SAS exome AF: 0.00207

Gnomad4 FIN exome AF: 0.00571

Gnomad4 NFE exome AF: 0.00585

Gnomad4 OTH exome AF: 0.00762

GnomAD4 genome AF: 0.00280 AC: 124 AN: 44275 Hom.: 0 Cov.: 16 AF XY: 0.00135 AC XY: 10 AN XY: 7391

Gnomad4 AFR AF: 0.00809

Gnomad4 AMR AF: 0.000585

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000847

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000879

Gnomad4 NFE AF: 0.0000471

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34350340; hg19: chrX-118971578;