chr21-43094667-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM5PP2PP3PP5BS2_Supporting
The NM_006758.3(U2AF1):āc.470A>Gā(p.Gln157Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (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: š 0.00010 ( 0 hom., cov: 8)
Exomes š: 0.000025 ( 0 hom. )
Consequence
U2AF1
NM_006758.3 missense
NM_006758.3 missense
Scores
8
6
2
Clinical Significance
Conservation
PhyloP100: 7.17
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a chain Splicing factor U2AF 35 kDa subunit (size 238) in uniprot entity U2AF1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006758.3
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-43094667-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376024.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant where missense usually causes diseases, U2AF1
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 21-43094667-T-C is Pathogenic according to our data. Variant chr21-43094667-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376023.Status of the report is no_assertion_criteria_provided, 0 stars.
BS2
High AC in GnomAd4 at 7 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
U2AF1 | NM_006758.3 | c.470A>G | p.Gln157Arg | missense_variant | 6/8 | ENST00000291552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
U2AF1 | ENST00000291552.9 | c.470A>G | p.Gln157Arg | missense_variant | 6/8 | 1 | NM_006758.3 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000102 AC: 7AN: 68374Hom.: 0 Cov.: 8
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251350Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135880
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GnomAD4 exome AF: 0.0000251 AC: 11AN: 437684Hom.: 0 Cov.: 5 AF XY: 0.0000391 AC XY: 9AN XY: 230238
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GnomAD4 genome AF: 0.000102 AC: 7AN: 68374Hom.: 0 Cov.: 8 AF XY: 0.000124 AC XY: 4AN XY: 32352
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
1.0
.;.;D;.
Vest4
MVP
MPC
2.8
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at