11-60902635-T-G

Position:

• chr11-60902635-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014502.5(PRPF19):​c.410A>C​(p.Gln137Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPF19 NM_014502.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.27

Genes affected

PRPF19 (HGNC:17896): (pre-mRNA processing factor 19) Enables identical protein binding activity and ubiquitin-ubiquitin ligase activity. Involved in several processes, including DNA damage checkpoint signaling; cellular protein metabolic process; and mRNA splicing, via spliceosome. Acts upstream of or within protein polyubiquitination. Located in cytoplasm; nuclear speck; and site of double-strand break. Part of Prp19 complex and U2-type catalytic step 2 spliceosome. Colocalizes with DNA replication factor A complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF19	NM_014502.5	c.410A>C	p.Gln137Pro	missense_variant	5/16	ENST00000227524.9	NP_055317.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF19	ENST00000227524.9	c.410A>C	p.Gln137Pro	missense_variant	5/16	1	NM_014502.5	ENSP00000227524.4
PRPF19	ENST00000541371.5	c.410A>C	p.Gln137Pro	missense_variant	5/10	3		ENSP00000440266.1
PRPF19	ENST00000546152.1	c.155A>C	p.Gln52Pro	missense_variant	6/8	5		ENSP00000446259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

The c.410A>C (p.Q137P) alteration is located in exon 5 (coding exon 5) of the PRPF19 gene. This alteration results from a A to C substitution at nucleotide position 410, causing the glutamine (Q) at amino acid position 137 to be replaced by a proline (P). 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	0.29
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	D;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.012	D;T;T
Polyphen		0.83	P;.;.
Vest4		0.61
MutPred		0.73		Gain of catalytic residue at P136 (P = 0.0107);Gain of catalytic residue at P136 (P = 0.0107);.;
MVP		0.64
MPC		1.7
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.70
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-60670107;