21-43104348-G-C

Variant names:

• chr21-43104348-G-C
• rs139959814
• NM_006758.3:c.99C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP2 PP3_Strong

The NM_006758.3(U2AF1):​c.99C>G​(p.Cys33Trp) variant causes a missense change involving the alteration of a non-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. Synonymous variant affecting the same amino acid position (i.e. C33C) has been classified as Benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: U2AF1 NM_006758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• 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: MetaRNN computational evidence supports a deleterious effect, 0.991

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	U2AF1	NM_006758.3	MANE Select	c.99C>G	p.Cys33Trp	missense	Exon 2 of 8	NP_006749.1	Q01081-1
	U2AF1	NM_001025203.1		c.99C>G	p.Cys33Trp	missense	Exon 2 of 8	NP_001020374.1	Q01081-2
	U2AF1	NM_001025204.2		c.-188C>G		5_prime_UTR	Exon 2 of 9	NP_001020375.1	Q01081-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	U2AF1	ENST00000291552.9	TSL:1 MANE Select	c.99C>G	p.Cys33Trp	missense	Exon 2 of 8	ENSP00000291552.4	Q01081-1
	U2AF1	ENST00000380276.6	TSL:1	c.99C>G	p.Cys33Trp	missense	Exon 2 of 8	ENSP00000369629.2	Q01081-2
	U2AF1	ENST00000459639.5	TSL:1	c.-121C>G		5_prime_UTR	Exon 1 of 7	ENSP00000418705.1	Q01081-4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		2.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.93		Gain of MoRF binding (P = 0.0136)
MVP		1.0
MPC		3.4
ClinPred		1.0	D
GERP RS		1.5
Varity_R		0.96
gMVP		1.0
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs139959814; hg19: chr21-44524458;