Genetic Variant NM_017619.4:c.574A>G (chr1-103536144-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017619.4(RNPC3):c.574A>G(p.Lys192Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,383,460 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: 0.000010 ( 0 hom. )

Consequence

RNPC3
NM_017619.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.24

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

isolated growth hormone deficiency, type 5
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
isolated growth hormone deficiency type IA
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RNPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017619.4. 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
	RNPC3	NM_017619.4	MANE Select	c.574A>G	p.Lys192Glu	missense	Exon 6 of 15	NP_060089.1	Q96LT9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RNPC3	ENST00000423855.7	TSL:1 MANE Select	c.574A>G	p.Lys192Glu	missense	Exon 6 of 15	ENSP00000391432.1	Q96LT9-1
RNPC3	ENST00000533099.5	TSL:5	c.574A>G	p.Lys192Glu	missense	Exon 7 of 16	ENSP00000432886.1	Q96LT9-1
RNPC3	ENST00000878138.1		c.574A>G	p.Lys192Glu	missense	Exon 6 of 15	ENSP00000548197.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000141

AC:

AN:

141596

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000344

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000101

AC:

AN:

1383460

Hom.:

Cov.:

AF XY:

0.00000879

AC XY:

AN XY:

682724

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31548

American (AMR)

AF:

0.00

AC:

AN:

35690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25158

East Asian (EAS)

AF:

0.00

AC:

AN:

35670

South Asian (SAS)

AF:

0.00

AC:

AN:

79186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

1077682

Other (OTH)

AF:

0.00

AC:

AN:

57854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.46

MetaSVM

Benign

-0.83

PhyloP100

8.2

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.28

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.011

Polyphen

0.99

Vest4

0.80

MutPred

0.34

Loss of ubiquitination at K192 (P = 0.0224)

MVP

0.52

MPC

0.51

ClinPred

0.82

GERP RS

5.4

Varity_R

0.39

gMVP

0.84

Mutation Taster

=42/58

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over