chr19-55669177-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_007279.3(U2AF2):c.1040C>T(p.Pro347Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. P347H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

U2AF2
NM_007279.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00700

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:

ENSG00000267523 (HGNC:):

ENSG00000267523 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.7134 (above the threshold of 3.09). Trascript score misZ: 6.409 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental delay, dysmorphic facies, and brain anomalies.

BP4

Computational evidence support a benign effect (MetaRNN=0.0547494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
U2AF2	NM_007279.3 link	c.1040C>T	p.Pro347Leu	missense_variant	Exon 10 of 12	ENST00000308924.9	NP_009210.1	P26368-1
U2AF2	XM_011526410.2 link	c.728C>T	p.Pro243Leu	missense_variant	Exon 11 of 13		XP_011524712.1
U2AF2	XM_047438120.1 link	c.548C>T	p.Pro183Leu	missense_variant	Exon 7 of 9		XP_047294076.1
U2AF2	NM_001012478.2 link	c.1032+8C>T		splice_region_variant, intron_variant	Intron 10 of 11		NP_001012496.1	P26368-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
U2AF2	ENST00000308924.9 link	c.1040C>T	p.Pro347Leu	missense_variant	Exon 10 of 12	1	NM_007279.3	ENSP00000307863.3		P26368-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461502

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111880

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.033

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.53

M_CAP

Benign

0.0088

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

PhyloP100

-0.0070

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.16

REVEL

Benign

0.11

Sift

Benign

0.68

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.092

MutPred

0.39

Loss of disorder (P = 0.0204);

MVP

0.043

MPC

1.3

ClinPred

0.092

GERP RS

-0.76

Varity_R

0.020

gMVP

0.39

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over