21-43093188-C-T

Position:

• chr21-43093188-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_006758.3(U2AF1):​c.637G>A​(p.Gly213Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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: 4.61

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]

U2AF1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24712873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
U2AF1	NM_006758.3	c.637G>A	p.Gly213Ser	missense_variant	8/8	ENST00000291552.9	NP_006749.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
U2AF1	ENST00000291552.9	c.637G>A	p.Gly213Ser	missense_variant	8/8	1	NM_006758.3	ENSP00000291552.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250030 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.637G>A (p.G213S) 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 637, causing the glycine (G) at amino acid position 213 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	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Benign	0.47
Eigen	Benign	0.057
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.1	.;L;L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.15	N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.79	T;T;T;T
Sift4G	Benign	0.59	T;T;T;T
Polyphen		1.0	.;.;D;.
Vest4		0.46
MutPred		0.26		.;Gain of phosphorylation at G213 (P = 1e-04);Gain of phosphorylation at G213 (P = 1e-04);.;
MVP		0.68
MPC		1.5
ClinPred		0.16	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.37

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: rs761520409; hg19: chr21-44513298; COSMIC: COSV52350416; COSMIC: COSV52350416;