21-43093182-C-T

Variant names:

• chr21-43093182-C-T
• rs1450304522
• NM_006758.3:c.643G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_006758.3(U2AF1):​c.643G>A​(p.Gly215Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: U2AF1 NM_006758.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43

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_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32032034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
U2AF1	NM_006758.3	c.643G>A	p.Gly215Ser	missense_variant	Exon 8 of 8	ENST00000291552.9	NP_006749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
U2AF1	ENST00000291552.9	c.643G>A	p.Gly215Ser	missense_variant	Exon 8 of 8	1	NM_006758.3	ENSP00000291552.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249506 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135264

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000468 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.643G>A (p.G215S) alteration is located in exon 8 (coding exon 8) of the U2AF1 gene. This alteration results from a G to A substitution at nucleotide position 643, causing the glycine (G) at amino acid position 215 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Benign	0.73
Eigen	Benign	0.10
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	.;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	0.90	.;L;L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.20	N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.64	T;T;T;T
Sift4G	Benign	0.37	T;T;T;T
Polyphen		1.0	.;.;D;.
Vest4		0.39
MutPred		0.35		.;Gain of phosphorylation at G215 (P = 2e-04);Gain of phosphorylation at G215 (P = 2e-04);.;
MVP		0.81
MPC		1.5
ClinPred		0.18	T
GERP RS		4.8
Varity_R		0.13
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs1450304522; hg19: chr21-44513292; COSMIC: COSV99373514; COSMIC: COSV99373514;