1-103536187-C-T

Position:

chr1-103536187-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_017619.4(RNPC3):c.617C>T(p.Pro206Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00137 in 1,534,818 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

RNPC3
NM_017619.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.99

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]

RNPC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.076382786).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000723 (110/152166) while in subpopulation NFE AF= 0.00135 (92/67974). AF 95% confidence interval is 0.00113. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNPC3	NM_017619.4 linkuse as main transcript	c.617C>T	p.Pro206Leu	missense_variant	6/15	ENST00000423855.7	NP_060089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNPC3	ENST00000423855.7 linkuse as main transcript	c.617C>T	p.Pro206Leu	missense_variant	6/15	1	NM_017619.4	ENSP00000391432	P4	Q96LT9-1
RNPC3	ENST00000533099.5 linkuse as main transcript	c.617C>T	p.Pro206Leu	missense_variant	7/16	5		ENSP00000432886	P4	Q96LT9-1
RNPC3	ENST00000524631.5 linkuse as main transcript	c.617C>T	p.Pro206Leu	missense_variant	6/15	2		ENSP00000437278	A1	Q96LT9-2
RNPC3	ENST00000527062.5 linkuse as main transcript	c.140C>T	p.Pro47Leu	missense_variant	6/8	5		ENSP00000436315

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000551

AC:

AN:

141604

Hom.:

AF XY:

0.000555

AC XY:

AN XY:

75734

show subpopulations

Gnomad AFR exome

AF:

0.000395

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000238

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00122

Gnomad OTH exome

AF:

0.000475

GnomAD4 exome

AF:

0.00144

AC:

1988

AN:

1382652

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

926

AN XY:

682372

show subpopulations

Gnomad4 AFR exome

AF:

0.000222

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.000278

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000286

Gnomad4 NFE exome

AF:

0.00173

Gnomad4 OTH exome

AF:

0.00188

GnomAD4 genome

AF:

0.000723

AC:

110

AN:

152166

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00135

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000808

Hom.:

Bravo

AF:

0.000722

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ExAC

AF:

0.000307

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.617C>T (p.P206L) alteration is located in exon 1 (coding exon 1) of the RNPC3 gene. This alteration results from a C to T substitution at nucleotide position 617, causing the proline (P) at amino acid position 206 to be replaced by a leucine (L). 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

Pathogenic

0.82

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;T;T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;.;D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.076

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.049

D;T;D;T

Polyphen

0.90

.;P;.;P

Vest4

0.64

MVP

0.26

MPC

0.44

ClinPred

0.18

GERP RS

5.5

Varity_R

0.23

gMVP

0.75

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over