chr10-11955227-T-C

Variant names:

• chr10-11955227-T-C
• rs74119913
• NM_015542.4:c.2850+5A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015542.4(UPF2):​c.2850+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,579,360 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (111 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (95 hom.)
• Consequence: UPF2 NM_015542.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005087
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.134

Genes affected

UPF2 (HGNC:17854): (UPF2 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. 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 in the perinuclear area. It interacts with translation release factors and the proteins that are functional homologs of yeast Upf1p and Upf3p. Two splice variants have been found for this gene; both variants encode the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-11955227-T-C is Benign according to our data. Variant chr10-11955227-T-C is described in ClinVar as [Benign]. Clinvar id is 790079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UPF2	NM_015542.4	c.2850+5A>G		splice_region_variant, intron_variant	Intron 14 of 21	ENST00000357604.10	NP_056357.1
UPF2	NM_080599.3	c.2850+5A>G		splice_region_variant, intron_variant	Intron 14 of 21		NP_542166.1
UPF2	XM_047424986.1	c.2850+5A>G		splice_region_variant, intron_variant	Intron 14 of 20		XP_047280942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UPF2	ENST00000357604.10	c.2850+5A>G		splice_region_variant, intron_variant	Intron 14 of 21	1	NM_015542.4	ENSP00000350221.5
UPF2	ENST00000356352.6	c.2850+5A>G		splice_region_variant, intron_variant	Intron 13 of 20	1		ENSP00000348708.2
UPF2	ENST00000397053.6	c.2850+5A>G		splice_region_variant, intron_variant	Intron 14 of 21	5		ENSP00000380244.2

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3342 AN: 152182 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00664 AC: 1562 AN: 235332 AF XY: 0.00503

Gnomad AFR exome AF: 0.0707

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000560

Gnomad OTH exome AF: 0.00527

GnomAD4 exome AF: 0.00273 AC: 3902 AN: 1427060 Hom.: 95 Cov.: 30 AF XY: 0.00246 AC XY: 1735 AN XY: 705378

Gnomad4 AFR exome AF: 0.0722 AC: 2332 AN: 32284

Gnomad4 AMR exome AF: 0.00593 AC: 238 AN: 40122

Gnomad4 ASJ exome AF: 0.0199 AC: 497 AN: 25004

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39094

Gnomad4 SAS exome AF: 0.000175 AC: 14 AN: 79998

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52662

Gnomad4 NFE exome AF: 0.000392 AC: 429 AN: 1093440

Gnomad4 Remaining exome AF: 0.00609 AC: 358 AN: 58808

GnomAD4 genome AF: 0.0220 AC: 3349 AN: 152300 Hom.: 111 Cov.: 32 AF XY: 0.0221 AC XY: 1643 AN XY: 74482

Gnomad4 AFR AF: 0.0726 AC: 0.0726494 AN: 0.0726494

Gnomad4 AMR AF: 0.0108 AC: 0.0108468 AN: 0.0108468

Gnomad4 ASJ AF: 0.0242 AC: 0.0241935 AN: 0.0241935

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000621 AC: 0.000621375 AN: 0.000621375

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000529 AC: 0.000529256 AN: 0.000529256

Gnomad4 OTH AF: 0.0189 AC: 0.0189215 AN: 0.0189215

Alfa AF: 0.0296 Hom.: 865

Bravo AF: 0.0251

Asia WGS AF: 0.00433 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.0
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.010
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

Publications

LitVar

Other links and lift over

dbSNP: rs74119913; hg19: chr10-11997226;