19-55660517-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_007279.3(U2AF2):​c.232C>A​(p.Arg78Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000012 in 834,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. R78C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: U2AF2 NM_007279.3 missense, splice_region
• Scores: Splicing: ADA: 0.02374
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 1 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=0.23448035).

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>A	p.Arg78Ser	missense splice_region	Exon 4 of 12	NP_009210.1	P26368-1
	U2AF2	NM_001012478.2		c.232C>A	p.Arg78Ser	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>A	p.Arg78Ser	missense splice_region	Exon 4 of 12	ENSP00000307863.3	P26368-1
	U2AF2	ENST00000450554.6	TSL:1	c.232C>A	p.Arg78Ser	missense splice_region	Exon 4 of 12	ENSP00000388475.1	P26368-2
	U2AF2	ENST00000890136.1		c.268C>A	p.Arg90Ser	missense splice_region	Exon 4 of 12	ENSP00000560195.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000120 AC: 1 AN: 834722 Hom.: 0 Cov.: 26 AF XY: 0.00000233 AC XY: 1 AN XY: 430002

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.0000157 AC: 1 AN: 63634

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: 0.00 AC: 0 AN: 593974

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	35
DANN	Uncertain	0.98
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.23
Sift	Benign	0.30	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.55
MutPred		0.38		Gain of phosphorylation at R78 (P = 0.0168)
MVP		0.068
MPC		1.4
ClinPred		0.80	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.58
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.024
dbscSNV1_RF	Benign	0.098
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: 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;