NM_006758.3:c.470A>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PP2PP3_ModeratePP5_ModerateBS2_Supporting

The NM_006758.3(U2AF1):c.470A>C(p.Gln157Pro) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 8)

Exomes 𝑓: 0.000030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

U2AF1
NM_006758.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter 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.

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

MetaRNN computational evidence supports a deleterious effect, 0.852

PP5

Variant 21-43094667-T-G is Pathogenic according to our data. 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.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
U2AF1	NM_006758.3 link	c.470A>C	p.Gln157Pro	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>C	p.Gln157Pro	missense_variant	Exon 6 of 8	1	NM_006758.3	ENSP00000291552.4		Q01081-1

Frequencies

GnomAD3 genomes

AF:

0.0000731

AC:

AN:

68372

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000818

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:

0.000115

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251350

AF XY:

0.0000442

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000297

AC:

AN:

437688

Hom.:

Cov.:

AF XY:

0.0000478

AC XY:

AN XY:

230238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

10406

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

34414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1684

European-Non Finnish (NFE)

AF:

0.0000428

AC:

AN:

256740

Other (OTH)

AF:

0.0000833

AC:

AN:

24018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000731

AC:

AN:

68372

Hom.:

Cov.:

AF XY:

0.0000618

AC XY:

AN XY:

32350

show subpopulations

African (AFR)

AF:

0.0000818

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:

0.000115

AC:

AN:

34904

Other (OTH)

AF:

0.00

AC:

AN:

808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

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.:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Mar 15, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PP4_MOD, PP3, PP2, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Pathogenic

0.85

D;D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

3.5

.;H;H;.

PhyloP100

7.2

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.6

D;D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.41

.;.;B;.

Vest4

0.86

MutPred

0.56

.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;

MVP

0.91

MPC

2.5

ClinPred

0.97

GERP RS

5.0

Varity_R

0.93

gMVP

1.0

Mutation Taster

=1/99

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over