Genetic Variant U2AF2:p.Arg78fs (chr19-55660513-CAGTCGTT-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_007279.3(U2AF2):c.231-2_235delAGTCGTT(p.Arg78fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

U2AF2
NM_007279.3 frameshift, splice_acceptor, splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 9.21

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: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.231-2_235delAGTCGTT	p.Arg78fs	frameshift splice_acceptor splice_region intron	Exon 4 of 12	NP_009210.1	P26368-1
	U2AF2	NM_001012478.2		c.231-2_235delAGTCGTT	p.Arg78fs	frameshift splice_acceptor splice_region intron	Exon 4 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.231-2_235delAGTCGTT	p.Arg78fs	frameshift splice_acceptor splice_region intron	Exon 4 of 12	ENSP00000307863.3	P26368-1
U2AF2	ENST00000450554.6	TSL:1	c.231-2_235delAGTCGTT	p.Arg78fs	frameshift splice_acceptor splice_region intron	Exon 4 of 12	ENSP00000388475.1	P26368-2
U2AF2	ENST00000890136.1		c.267-2_271delAGTCGTT	p.Arg90fs	frameshift splice_acceptor splice_region intron	Exon 4 of 12	ENSP00000560195.1

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

355

AN:

147044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00271

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00238

Gnomad EAS

AF:

0.000788

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.00225

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00280

Gnomad OTH

AF:

0.00250

GnomAD2 exomes

AF:

0.00278

AC:

638

AN:

229266

AF XY:

0.00265

show subpopulations

Gnomad AFR exome

AF:

0.000579

Gnomad AMR exome

AF:

0.00569

Gnomad ASJ exome

AF:

0.00494

Gnomad EAS exome

AF:

0.00126

Gnomad FIN exome

AF:

0.00623

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.00526

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00108

AC:

1481

AN:

1377218

Hom.:

AF XY:

0.00112

AC XY:

765

AN XY:

685366

show subpopulations

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

African (AFR)

AF:

0.00175

AC:

AN:

31436

American (AMR)

AF:

0.00955

AC:

365

AN:

38232

Ashkenazi Jewish (ASJ)

AF:

0.00285

AC:

AN:

23874

East Asian (EAS)

AF:

0.000154

AC:

AN:

39000

South Asian (SAS)

AF:

0.00349

AC:

270

AN:

77418

European-Finnish (FIN)

AF:

0.00219

AC:

111

AN:

50710

Middle Eastern (MID)

AF:

0.00202

AC:

AN:

5440

European-Non Finnish (NFE)

AF:

0.000476

AC:

502

AN:

1054130

Other (OTH)

AF:

0.00163

AC:

AN:

56978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.293

Heterozygous variant carriers

153

306

460

613

766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00241

AC:

355

AN:

147142

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

173

AN XY:

71906

show subpopulations

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

African (AFR)

AF:

0.00270

AC:

108

AN:

39978

American (AMR)

AF:

0.00144

AC:

AN:

14624

Ashkenazi Jewish (ASJ)

AF:

0.00238

AC:

AN:

3360

East Asian (EAS)

AF:

0.000790

AC:

AN:

5062

South Asian (SAS)

AF:

0.000211

AC:

AN:

4736

European-Finnish (FIN)

AF:

0.00225

AC:

AN:

10230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00281

AC:

185

AN:

65944

Other (OTH)

AF:

0.00248

AC:

AN:

2020

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

100

151

201

251

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:

0.0155

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.2

Mutation Taster

=13/187

disease causing (fs/PTC)

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over