Genetic Variant U2AF2:p.Arg37Leu (chr19-55659270-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_007279.3(U2AF2):c.110G>T(p.Arg37Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R37H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

U2AF2
NM_007279.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.43

Publications

0 publications found

Variant links:

Genes affected

U2AF2 (HGNC:23156): (U2 small nuclear RNA auxiliary factor 2) U2 auxiliary factor (U2AF), comprised of a large and a small subunit, is a non-snRNP protein required for the binding of U2 snRNP to the pre-mRNA branch site. This gene encodes the U2AF large subunit which contains a sequence-specific RNA-binding region with 3 RNA recognition motifs and an Arg/Ser-rich domain necessary for splicing. The large subunit binds to the polypyrimidine tract of introns early during spliceosome assembly. Multiple transcript variants have been detected for this gene, but the full-length natures of only two have been determined to date. [provided by RefSeq, Jul 2008]

U2AF2 Gene-Disease associations (from GenCC):

developmental delay, dysmorphic facies, and brain anomalies
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

U2AF2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.7134 (above the threshold of 3.09). Trascript score misZ: 6.409 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental delay, dysmorphic facies, and brain anomalies.

BP4

Computational evidence support a benign effect (MetaRNN=0.23115268).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007279.3. 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
	U2AF2	NM_007279.3	MANE Select	c.110G>T	p.Arg37Leu	missense	Exon 2 of 12	NP_009210.1	P26368-1
	U2AF2	NM_001012478.2		c.110G>T	p.Arg37Leu	missense	Exon 2 of 12	NP_001012496.1	P26368-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
U2AF2	ENST00000308924.9	TSL:1 MANE Select	c.110G>T	p.Arg37Leu	missense	Exon 2 of 12	ENSP00000307863.3	P26368-1
U2AF2	ENST00000450554.6	TSL:1	c.110G>T	p.Arg37Leu	missense	Exon 2 of 12	ENSP00000388475.1	P26368-2
U2AF2	ENST00000890136.1		c.110G>T	p.Arg37Leu	missense	Exon 2 of 12	ENSP00000560195.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1450058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720460

African (AFR)

AF:

0.00

AC:

AN:

32784

American (AMR)

AF:

0.00

AC:

AN:

43876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25794

East Asian (EAS)

AF:

0.00

AC:

AN:

38854

South Asian (SAS)

AF:

0.00

AC:

AN:

85240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105858

Other (OTH)

AF:

0.00

AC:

AN:

59644

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

-0.0099

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

7.4

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.13

Sift

Uncertain

0.012

Sift4G

Uncertain

0.0050

Polyphen

0.063

Vest4

0.53

MutPred

0.33

Gain of catalytic residue at R37 (P = 0.0291)

MVP

0.082

MPC

1.6

ClinPred

0.99

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.52

Mutation Taster

=70/30

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over