rs545361014

Variant names:

• chr6-158980769-C-T
• rs545361014
• NM_031924.8:c.859+5G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_Moderate BS1_Supporting

The NM_031924.8(RSPH3):​c.859+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,610,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: RSPH3 NM_031924.8 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61
• Publications: 0 publications found

Genes affected

RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

RSPH3 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 32

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000105 (16/152270) while in subpopulation AMR AF = 0.000915 (14/15294). AF 95% confidence interval is 0.000553. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031924.8. 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
	RSPH3	NM_031924.8	MANE Select	c.859+5G>A		splice_region intron	N/A	NP_114130.4
	RSPH3	NM_001346418.1		c.997+5G>A		splice_region intron	N/A	NP_001333347.1
	RSPH3	NR_144434.1		n.1496+5G>A		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.859+5G>A		splice_region intron	N/A	ENSP00000356036.1
	RSPH3	ENST00000884885.1		c.691+5G>A		splice_region intron	N/A	ENSP00000554944.1
	RSPH3	ENST00000449822.6	TSL:2	c.571+5G>A		splice_region intron	N/A	ENSP00000393195.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249796 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000960 AC: 14 AN: 1458008 Hom.: 0 Cov.: 30 AF XY: 0.00000965 AC XY: 7 AN XY: 725058

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.0000897 AC: 4 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1108904

Other (OTH) AF: 0.0000166 AC: 1 AN: 60230

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.000915 AC: 14 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000181

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia 32 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Benign	0.97
PhyloP100		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.12		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: rs545361014; hg19: chr6-159401801; COSMIC: COSV51921131; COSMIC: COSV51921131;