chr19-55660517-C-T

Variant names:

• chr19-55660517-C-T
• rs1984111007
• NM_007279.3:c.232C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BS2

The NM_007279.3(U2AF2):​c.232C>T​(p.Arg78Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000108 in 834,730 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: U2AF2 NM_007279.3 missense, splice_region
• Scores: Splicing: ADA: 0.6292
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52
• 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.

• 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.
• BS2: High AC in GnomAdExome4 at 9 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.232C>T	p.Arg78Cys	missense splice_region	Exon 4 of 12	NP_009210.1	P26368-1
	U2AF2	NM_001012478.2		c.232C>T	p.Arg78Cys	missense splice_region	Exon 4 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.232C>T	p.Arg78Cys	missense splice_region	Exon 4 of 12	ENSP00000307863.3	P26368-1
	U2AF2	ENST00000450554.6	TSL:1	c.232C>T	p.Arg78Cys	missense splice_region	Exon 4 of 12	ENSP00000388475.1	P26368-2
	U2AF2	ENST00000890136.1		c.268C>T	p.Arg90Cys	missense splice_region	Exon 4 of 12	ENSP00000560195.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.0000108 AC: 9 AN: 834730 Hom.: 0 Cov.: 26 AF XY: 0.00000698 AC XY: 3 AN XY: 430008

African (AFR) AF: 0.00 AC: 0 AN: 19718

American (AMR) AF: 0.00 AC: 0 AN: 31318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16682

East Asian (EAS) AF: 0.00 AC: 0 AN: 28082

South Asian (SAS) AF: 0.00 AC: 0 AN: 63638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4066

European-Non Finnish (NFE) AF: 0.0000152 AC: 9 AN: 593978

Other (OTH) AF: 0.00 AC: 0 AN: 36144

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

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	0.17
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.14
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.010	D
Polyphen		0.91	P
Vest4		0.57
MutPred		0.42		Loss of solvent accessibility (P = 0.001)
MVP		0.068
MPC		2.1
ClinPred		0.96	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.54
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.63
dbscSNV1_RF	Benign	0.62
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: rs1984111007; hg19: chr19-56171883;