rs371769427

chr21-43104346-G-Cchr21-43104346-G-Achr21-43104346-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM5 PP2 PP3_Moderate

The NM_006758.3(U2AF1):c.101C>G(p.Ser34Cys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. S34F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: U2AF1 NM_006758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.05

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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 chr21-43104346-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376025.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, U2AF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
U2AF1	NM_006758.3	c.101C>G	p.Ser34Cys	missense_variant	2/8	ENST00000291552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
U2AF1	ENST00000291552.9	c.101C>G	p.Ser34Cys	missense_variant	2/8	1	NM_006758.3	P3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	30
Dann	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.67
MutPred		0.85		Loss of disorder (P = 0.0182);Loss of disorder (P = 0.0182);
MVP		0.78
MPC		2.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-44524456;