rs778506096

Variant names:

• chr1-103533856-A-C
• rs778506096
• NM_017619.4:c.358A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-103533856-A-C
• chr1-103533856-A-G
• chr1-103533856-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017619.4(RNPC3):​c.358A>C​(p.Arg120Arg) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000163 in 1,226,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: RNPC3 NM_017619.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.8733
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).

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.358A>C	p.Arg120Arg	splice_region synonymous	Exon 3 of 15	NP_060089.1	Q96LT9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNPC3	ENST00000423855.7	TSL:1 MANE Select	c.358A>C	p.Arg120Arg	splice_region synonymous	Exon 3 of 15	ENSP00000391432.1	Q96LT9-1
	RNPC3	ENST00000527062.5	TSL:5	c.-120A>C		splice_region	Exon 3 of 8	ENSP00000436315.1	E9PPV2
	RNPC3	ENST00000533099.5	TSL:5	c.358A>C	p.Arg120Arg	splice_region synonymous	Exon 4 of 16	ENSP00000432886.1	Q96LT9-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1226386 Hom.: 0 Cov.: 20 AF XY: 0.00000163 AC XY: 1 AN XY: 613172

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27534

American (AMR) AF: 0.00 AC: 0 AN: 33798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24124

East Asian (EAS) AF: 0.00 AC: 0 AN: 35024

South Asian (SAS) AF: 0.00 AC: 0 AN: 75524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5338

European-Non Finnish (NFE) AF: 0.00000213 AC: 2 AN: 937588

Other (OTH) AF: 0.00 AC: 0 AN: 52610

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.94
PhyloP100		6.7
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Benign	0.71
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

Other links and lift over

dbSNP: rs778506096; hg19: chr1-104076478;