Genetic Variant U2AF2:p.Arg81His (chr19-55660527-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007279.3(U2AF2):c.242G>A(p.Arg81His) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 427,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

U2AF2
NM_007279.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.35

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09355399).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
U2AF2	NM_007279.3 link	c.242G>A	p.Arg81His	missense_variant	Exon 4 of 12	ENST00000308924.9	NP_009210.1	P26368-1
U2AF2	NM_001012478.2 link	c.242G>A	p.Arg81His	missense_variant	Exon 4 of 12		NP_001012496.1	P26368-2
U2AF2	XM_011526410.2 link	c.-71G>A		5_prime_UTR_variant	Exon 5 of 13		XP_011524712.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
U2AF2	ENST00000308924.9 link	c.242G>A	p.Arg81His	missense_variant	Exon 4 of 12	1	NM_007279.3	ENSP00000307863.3		P26368-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000132

AC:

AN:

151560

Hom.:

AF XY:

0.0000121

AC XY:

AN XY:

82646

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000259

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

427396

Hom.:

Cov.:

AF XY:

0.0000183

AC XY:

AN XY:

219040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000911

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000195

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.242G>A (p.R81H) alteration is located in exon 4 (coding exon 4) of the U2AF2 gene. This alteration results from a G to A substitution at nucleotide position 242, causing the arginine (R) at amino acid position 81 to be replaced by a histidine (H). 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

Benign

0.098

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.046

.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.037

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.40

N;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.091

Sift

Benign

0.59

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.0010

B;B

Vest4

0.17

MutPred

0.42

Loss of MoRF binding (P = 0.0911);Loss of MoRF binding (P = 0.0911);

MVP

0.043

MPC

1.3

ClinPred

0.40

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.064

gMVP

0.12

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over