1-103533873-A-G

Variant names:

• chr1-103533873-A-G
• rs6702220
• NM_017619.4:c.359+16A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017619.4(RNPC3):​c.359+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 1,192,612 control chromosomes in the GnomAD database, including 228,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35413 hom., cov: 29)
  • Exomes 𝑓: 0.60 (193066 hom.)
• Consequence: RNPC3 NM_017619.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.937
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-103533873-A-G is Benign according to our data. Variant chr1-103533873-A-G is described in ClinVar as Benign. ClinVar VariationId is 1327963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

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.359+16A>G		intron	N/A	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.359+16A>G		intron	N/A	ENSP00000391432.1	Q96LT9-1
	RNPC3	ENST00000533099.5	TSL:5	c.359+16A>G		intron	N/A	ENSP00000432886.1	Q96LT9-1
	RNPC3	ENST00000878138.1		c.359+16A>G		intron	N/A	ENSP00000548197.1

Frequencies

GnomAD3 genomes AF: 0.673 AC: 101817 AN: 151210 Hom.: 35380 Cov.: 29

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.628

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.695

GnomAD2 exomes AF: 0.621 AC: 83678 AN: 134736 AF XY: 0.624

Gnomad AFR exome AF: 0.854

Gnomad AMR exome AF: 0.578

Gnomad ASJ exome AF: 0.668

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.592

Gnomad NFE exome AF: 0.640

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.604 AC: 629219 AN: 1041284 Hom.: 193066 Cov.: 14 AF XY: 0.606 AC XY: 320593 AN XY: 528886

African (AFR) AF: 0.846 AC: 20102 AN: 23770

American (AMR) AF: 0.575 AC: 19063 AN: 33148

Ashkenazi Jewish (ASJ) AF: 0.660 AC: 15035 AN: 22772

East Asian (EAS) AF: 0.339 AC: 11621 AN: 34278

South Asian (SAS) AF: 0.619 AC: 44351 AN: 71596

European-Finnish (FIN) AF: 0.586 AC: 20326 AN: 34708

Middle Eastern (MID) AF: 0.729 AC: 3588 AN: 4922

European-Non Finnish (NFE) AF: 0.606 AC: 466171 AN: 769622

Other (OTH) AF: 0.623 AC: 28962 AN: 46468

GnomAD4 genome AF: 0.673 AC: 101905 AN: 151328 Hom.: 35413 Cov.: 29 AF XY: 0.666 AC XY: 49297 AN XY: 73968

African (AFR) AF: 0.843 AC: 34818 AN: 41316

American (AMR) AF: 0.610 AC: 9282 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2314 AN: 3466

East Asian (EAS) AF: 0.372 AC: 1905 AN: 5126

South Asian (SAS) AF: 0.629 AC: 3025 AN: 4812

European-Finnish (FIN) AF: 0.570 AC: 5956 AN: 10442

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42494 AN: 67650

Other (OTH) AF: 0.691 AC: 1446 AN: 2092

Alfa AF: 0.656 Hom.: 6072

Bravo AF: 0.683

Asia WGS AF: 0.561 AC: 1951 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Isolated growth hormone deficiency, type 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.2
DANN	Benign	0.69
PhyloP100		0.94
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs6702220; hg19: chr1-104076495; COSMIC: COSV71077061; COSMIC: COSV71077061;