10-11931759-C-T

Position:

• chr10-11931759-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015542.4(UPF2):​c.3570G>A​(p.Met1190Ile) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: UPF2 NM_015542.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24400494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UPF2	NM_015542.4	c.3570G>A	p.Met1190Ile	missense_variant	20/22	ENST00000357604.10
UPF2	NM_080599.3	c.3570G>A	p.Met1190Ile	missense_variant	20/22
UPF2	XM_047424986.1	c.3570G>A	p.Met1190Ile	missense_variant	20/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UPF2	ENST00000357604.10	c.3570G>A	p.Met1190Ile	missense_variant	20/22	1	NM_015542.4	P1
UPF2	ENST00000356352.6	c.3570G>A	p.Met1190Ile	missense_variant	19/21	1		P1
UPF2	ENST00000397053.6	c.3570G>A	p.Met1190Ile	missense_variant	20/22	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.3570G>A (p.M1190I) alteration is located in exon 20 (coding exon 19) of the UPF2 gene. This alteration results from a G to A substitution at nucleotide position 3570, causing the methionine (M) at amino acid position 1190 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.058	T;T;T
Eigen	Benign	-0.098
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	.;.;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.19	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.033	B;B;B
Vest4		0.41
MutPred		0.81		Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);
MVP		0.49
MPC		0.70
ClinPred		0.49	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-11973758;