1-103536183-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_017619.4(RNPC3):​c.613C>T​(p.Arg205*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,535,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R205R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

RNPC3
NM_017619.4 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 2.53
Variant links:
Genes affected
RNPC3 (HGNC:18666): (RNA binding region (RNP1, RRM) containing 3) Two types of spliceosomes catalyze splicing of pre-mRNAs. The major U2-type spliceosome is found in all eukaryotes and removes U2-type introns, which represent more than 99% of pre-mRNA introns. The minor U12-type spliceosome is found in some eukaryotes and removes U12-type introns, which are rare and have distinct splice consensus signals. The U12-type spliceosome consists of several small nuclear RNAs and associated proteins. This gene encodes a 65K protein that is a component of the U12-type spliceosome. This protein contains two RNA recognition motifs (RRMs), suggesting that it may contact one of the small nuclear RNAs of the minor spliceosome. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-103536183-C-T is Pathogenic according to our data. Variant chr1-103536183-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1064669.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RNPC3NM_017619.4 linkc.613C>T p.Arg205* stop_gained Exon 6 of 15 ENST00000423855.7 NP_060089.1 Q96LT9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RNPC3ENST00000423855.7 linkc.613C>T p.Arg205* stop_gained Exon 6 of 15 1 NM_017619.4 ENSP00000391432.1 Q96LT9-1
RNPC3ENST00000533099.5 linkc.613C>T p.Arg205* stop_gained Exon 7 of 16 5 ENSP00000432886.1 Q96LT9-1
RNPC3ENST00000524631.5 linkc.613C>T p.Arg205* stop_gained Exon 6 of 15 2 ENSP00000437278.1 Q96LT9-2
RNPC3ENST00000527062.5 linkc.136C>T p.Arg46* stop_gained Exon 6 of 8 5 ENSP00000436315.1 E9PPV2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152068
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000535
AC:
74
AN:
1382972
Hom.:
0
Cov.:
29
AF XY:
0.0000484
AC XY:
33
AN XY:
682488
show subpopulations
Gnomad4 AFR exome
AF:
0.0000634
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000505
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000622
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74394
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000529

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Isolated growth hormone deficiency, type 5 Pathogenic:1
Nov 05, 2021
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Pathogenic:1
May 14, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32462814, Gucev2015[Poster], 34906446) -

Decreased response to growth hormone stimulation test Pathogenic:1
Apr 05, 2021
Department of Pediatric Endocrinology, Ondokuz Mayis University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
37
DANN
Uncertain
0.98
Eigen
Benign
0.038
Eigen_PC
Benign
-0.19
FATHMM_MKL
Uncertain
0.84
D
Vest4
0.54
GERP RS
1.4

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs939646611; hg19: chr1-104078805; API