NM_006758.3:c.470A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5PP2PP3

The NM_006758.3(U2AF1):c.470A>G(p.Gln157Arg) variant causes a missense change. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q157P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., cov: 8)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

U2AF1
NM_006758.3 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.17

Publications

152 publications found

Variant links:

Genes affected

U2AF1 (HGNC:12453): (U2 small nuclear RNA auxiliary factor 1) This gene belongs to the splicing factor SR family of genes. U2 auxiliary factor, comprising 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 small subunit which plays a critical role in both constitutive and enhancer-dependent RNA splicing by directly mediating interactions between the large subunit and proteins bound to the enhancers. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

U2AF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43094667-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 376024.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.8478 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09).

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
U2AF1	NM_006758.3 link	c.470A>G	p.Gln157Arg	missense_variant	Exon 6 of 8	ENST00000291552.9	NP_006749.1	Q01081-1Q7Z780

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
U2AF1	ENST00000291552.9 link	c.470A>G	p.Gln157Arg	missense_variant	Exon 6 of 8	1	NM_006758.3	ENSP00000291552.4		Q01081-1

Frequencies

GnomAD3 genomes

AF:

0.000102

AC:

AN:

68374

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000172

Gnomad OTH

AF:

0.00124

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251350

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000251

AC:

AN:

437684

Hom.:

Cov.:

AF XY:

0.0000391

AC XY:

AN XY:

230238

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000961

AC:

AN:

10404

American (AMR)

AF:

0.0000543

AC:

AN:

18402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13752

East Asian (EAS)

AF:

0.00

AC:

AN:

31470

South Asian (SAS)

AF:

0.00

AC:

AN:

46802

European-Finnish (FIN)

AF:

0.0000291

AC:

AN:

34414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1684

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

256738

Other (OTH)

AF:

0.0000833

AC:

AN:

24018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000108512), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.357

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000102

AC:

AN:

68374

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

32352

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

12228

American (AMR)

AF:

0.00

AC:

AN:

5690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2084

East Asian (EAS)

AF:

0.00

AC:

AN:

4184

South Asian (SAS)

AF:

0.00

AC:

AN:

2422

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

164

European-Non Finnish (NFE)

AF:

0.000172

AC:

AN:

34906

Other (OTH)

AF:

0.00124

AC:

AN:

808

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0116187), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.382

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Pathogenic:1

Oct 02, 2014

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.0

.;M;M;.

PhyloP100

7.2

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.8

D;D;D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;.;D;.

Vest4

0.77

MVP

0.92

MPC

2.8

ClinPred

0.94

GERP RS

5.0

Varity_R

0.77

gMVP

0.99

Mutation Taster

=16/84

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.79

Position offset: 0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over