rs371246226

Variant names:

• chr21-43094667-T-A
• rs371246226
• NM_006758.3:c.470A>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43094667-T-A
• chr21-43094667-T-C
• chr21-43094667-T-G

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.470A>T​(p.Gln157Leu) variant causes a missense change. 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. Q157P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 8)
• Consequence: U2AF1 NM_006758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• 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: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
U2AF1	NM_006758.3	c.470A>T	p.Gln157Leu	missense_variant	Exon 6 of 8	ENST00000291552.9	NP_006749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
U2AF1	ENST00000291552.9	c.470A>T	p.Gln157Leu	missense_variant	Exon 6 of 8	1	NM_006758.3	ENSP00000291552.4

Frequencies

GnomAD3 genomes Cov.: 8

GnomAD4 exome Cov.: 5

GnomAD4 genome Cov.: 8

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.1	.;M;M;.
PhyloP100		7.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;T;T;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.62	.;.;P;.
Vest4		0.75
MutPred		0.57		.;Loss of catalytic residue at Q157 (P = 0.0269);Loss of catalytic residue at Q157 (P = 0.0269);.;
MVP		0.83
MPC		1.9
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.52
gMVP		0.99
Mutation Taster		=1/99	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: rs371246226; hg19: chr21-44514777;