21-43094667-T-C

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. Variant has been reported in ClinVar as (no stars). 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

Not reported in ClinVar

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:

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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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006758.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
U2AF1	NM_006758.3	MANE Select	c.470A>G	p.Gln157Arg	missense	Exon 6 of 8	NP_006749.1	Q01081-1
U2AF1	NM_001025203.1		c.470A>G	p.Gln157Arg	missense	Exon 6 of 8	NP_001020374.1	Q01081-2
U2AF1	NM_001025204.2		c.251A>G	p.Gln84Arg	missense	Exon 7 of 9	NP_001020375.1	Q01081-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
U2AF1	ENST00000291552.9	TSL:1 MANE Select	c.470A>G	p.Gln157Arg	missense	Exon 6 of 8	ENSP00000291552.4	Q01081-1
U2AF1	ENST00000380276.6	TSL:1	c.470A>G	p.Gln157Arg	missense	Exon 6 of 8	ENSP00000369629.2	Q01081-2
U2AF1	ENST00000459639.5	TSL:1	c.251A>G	p.Gln84Arg	missense	Exon 5 of 7	ENSP00000418705.1	Q01081-4

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.0

PhyloP100

7.2

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over