chr19-55661071-C-T

Variant names:

• chr19-55661071-C-T
• NM_007279.3:c.368C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PP2 PP5_Moderate BP4

The NM_007279.3(U2AF2):​c.368C>T​(p.Pro123Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: U2AF2 NM_007279.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.04
• 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 4 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.
• PP5: Variant 19-55661071-C-T is Pathogenic according to our data. Variant chr19-55661071-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3769848.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26487836). . Strength limited to SUPPORTING due to the PP5.

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.368C>T	p.Pro123Leu	missense	Exon 5 of 12	NP_009210.1	P26368-1
	U2AF2	NM_001012478.2		c.368C>T	p.Pro123Leu	missense	Exon 5 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.368C>T	p.Pro123Leu	missense	Exon 5 of 12	ENSP00000307863.3	P26368-1
	U2AF2	ENST00000450554.6	TSL:1	c.368C>T	p.Pro123Leu	missense	Exon 5 of 12	ENSP00000388475.1	P26368-2
	U2AF2	ENST00000890136.1		c.404C>T	p.Pro135Leu	missense	Exon 5 of 12	ENSP00000560195.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.17
Sift	Uncertain	0.016	D
Sift4G	Benign	0.079	T
Polyphen		0.38	B
Vest4		0.46
MutPred		0.41		Loss of disorder (P = 0.0184)
MVP		0.043
MPC		2.0
ClinPred		0.97	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.29
gMVP		0.83
Mutation Taster		=81/19	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

hg19: chr19-56172437;