21-43094667-TG-AA

Variant names:

• chr21-43094667-TG-AA
• NM_006758.3:c.469_470delCAinsTT
• U2AF1 p.Gln157Leu

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5 PP2 PP3

The NM_006758.3(U2AF1):​c.469_470delCAinsTT​(p.Gln157Leu) variant causes a missense change involving the alteration of a conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. Q157R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 8)
• Consequence: U2AF1 NM_006758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.96
• 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 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43094667-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 376024.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.469_470delCAinsTT	p.Gln157Leu	missense	N/A	NP_006749.1	Q01081-1
	U2AF1	NM_001025203.1		c.469_470delCAinsTT	p.Gln157Leu	missense	N/A	NP_001020374.1	Q01081-2
	U2AF1	NM_001025204.2		c.250_251delCAinsTT	p.Gln84Leu	missense	N/A	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.469_470delCAinsTT	p.Gln157Leu	missense	N/A	ENSP00000291552.4	Q01081-1
	U2AF1	ENST00000380276.6	TSL:1	c.469_470delCAinsTT	p.Gln157Leu	missense	N/A	ENSP00000369629.2	Q01081-2
	U2AF1	ENST00000459639.5	TSL:1	c.250_251delCAinsTT	p.Gln84Leu	missense	N/A	ENSP00000418705.1	Q01081-4

Frequencies

GnomAD3 genomes Cov.: 8

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-44514777;