14-45114909-C-A

Position:

• chr14-45114909-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_017922.4(PRPF39):​c.2006C>A​(p.Thr669Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000486 in 1,440,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: PRPF39 NM_017922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.50

Genes affected

PRPF39 (HGNC:20314): (pre-mRNA processing factor 39) Predicted to be involved in mRNA 5'-splice site recognition. Predicted to be part of U1 snRNP; U2-type prespliceosome; and commitment complex. [provided by Alliance of Genome Resources, Apr 2022]

PRPF39 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF39	NM_017922.4	c.2006C>A	p.Thr669Asn	missense_variant	14/14	ENST00000355765.11	NP_060392.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF39	ENST00000355765.11	c.2006C>A	p.Thr669Asn	missense_variant	14/14	1	NM_017922.4	ENSP00000348010.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249624 Hom.: 0 AF XY: 0.0000371 AC XY: 5 AN XY: 134948

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1440410 Hom.: 0 Cov.: 29 AF XY: 0.00000697 AC XY: 5 AN XY: 717676

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.2006C>A (p.T669N) alteration is located in exon 14 (coding exon 13) of the PRPF39 gene. This alteration results from a C to A substitution at nucleotide position 2006, causing the threonine (T) at amino acid position 669 to be replaced by an asparagine (N). 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	0.19
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.33		Loss of glycosylation at T669 (P = 4e-04);
MVP		0.19
MPC		0.53
ClinPred		0.29	T
GERP RS		5.7
Varity_R		0.24
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs764441033; hg19: chr14-45584112;