chr19-55659293-G-A

Variant names:

• chr19-55659293-G-A
• rs11558805
• NM_007279.3:c.133G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Moderate BS2

The NM_007279.3(U2AF2):​c.133G>A​(p.Asp45Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,445,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: U2AF2 NM_007279.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.28
• Publications: 0 publications found

Genes affected

U2AF2 (HGNC:23156): (U2 small nuclear RNA auxiliary factor 2) U2 auxiliary factor (U2AF), comprised of 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 U2AF large subunit which contains a sequence-specific RNA-binding region with 3 RNA recognition motifs and an Arg/Ser-rich domain necessary for splicing. The large subunit binds to the polypyrimidine tract of introns early during spliceosome assembly. Multiple transcript variants have been detected for this gene, but the full-length natures of only two have been determined to date. [provided by RefSeq, Jul 2008]

U2AF2 Gene-Disease associations (from GenCC):

• developmental delay, dysmorphic facies, and brain anomalies

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 4.7134 (above the threshold of 3.09). Trascript score misZ: 6.409 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental delay, dysmorphic facies, and brain anomalies.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18563354).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007279.3. 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
	U2AF2	NM_007279.3	MANE Select	c.133G>A	p.Asp45Asn	missense	Exon 2 of 12	NP_009210.1	P26368-1
	U2AF2	NM_001012478.2		c.133G>A	p.Asp45Asn	missense	Exon 2 of 12	NP_001012496.1	P26368-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	U2AF2	ENST00000308924.9	TSL:1 MANE Select	c.133G>A	p.Asp45Asn	missense	Exon 2 of 12	ENSP00000307863.3	P26368-1
	U2AF2	ENST00000450554.6	TSL:1	c.133G>A	p.Asp45Asn	missense	Exon 2 of 12	ENSP00000388475.1	P26368-2
	U2AF2	ENST00000890136.1		c.133G>A	p.Asp45Asn	missense	Exon 2 of 12	ENSP00000560195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000911 AC: 2 AN: 219608 AF XY: 0.00000825

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000208

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1445702 Hom.: 0 Cov.: 30 AF XY: 0.00000418 AC XY: 3 AN XY: 717758

African (AFR) AF: 0.00 AC: 0 AN: 32742

American (AMR) AF: 0.00 AC: 0 AN: 43282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25672

East Asian (EAS) AF: 0.00 AC: 0 AN: 38804

South Asian (SAS) AF: 0.00 AC: 0 AN: 84692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103612

Other (OTH) AF: 0.00 AC: 0 AN: 59488

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000169 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.14
Sift	Benign	0.030	D
Sift4G	Benign	0.061	T
Polyphen		0.71	P
Vest4		0.34
MutPred		0.18		Loss of stability (P = 0.128)
MVP		0.17
MPC		1.0
ClinPred		0.47	T
GERP RS		2.9
Varity_R		0.14
gMVP		0.38
Mutation Taster		=83/17	polymorphism

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: rs11558805; hg19: chr19-56170659; COSMIC: COSV58275717;