chr14-45096113-T-C

Variant names:

• chr14-45096113-T-C
• NM_017922.4:c.335T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017922.4(PRPF39):​c.335T>C​(p.Met112Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,419,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PRPF39 NM_017922.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059698194).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017922.4. 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
	PRPF39	NM_017922.4	MANE Select	c.335T>C	p.Met112Thr	missense	Exon 3 of 14	NP_060392.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPF39	ENST00000355765.11	TSL:1 MANE Select	c.335T>C	p.Met112Thr	missense	Exon 3 of 14	ENSP00000348010.6	Q86UA1-1
	PRPF39	ENST00000931178.1		c.335T>C	p.Met112Thr	missense	Exon 3 of 14	ENSP00000601237.1
	PRPF39	ENST00000905876.1		c.335T>C	p.Met112Thr	missense	Exon 3 of 14	ENSP00000575935.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1419224 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702096

African (AFR) AF: 0.00 AC: 0 AN: 32332

American (AMR) AF: 0.00 AC: 0 AN: 38404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25440

East Asian (EAS) AF: 0.00 AC: 0 AN: 37818

South Asian (SAS) AF: 0.00 AC: 0 AN: 80646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089018

Other (OTH) AF: 0.00 AC: 0 AN: 58898

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.68
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N
PhyloP100		2.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.99	N
REVEL	Benign	0.054
Sift	Benign	0.66	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.36		Gain of catalytic residue at H110 (P = 0.0211)
MVP		0.19
MPC		0.53
ClinPred		0.086	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.15
Mutation Taster		=95/5	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: chr14-45565316;