NM_031924.8:c.703C>T

Variant names:

• chr6-158980930-G-A
• rs778108869
• NM_031924.8:c.703C>T

Variant summary

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

The NM_031924.8(RSPH3):​c.703C>T​(p.Arg235Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R235H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RSPH3 NM_031924.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12
• Publications: 1 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: ClinGen, PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

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.703C>T	p.Arg235Cys	missense	Exon 6 of 8	NP_114130.4
	RSPH3	NM_001346418.1		c.841C>T	p.Arg281Cys	missense	Exon 4 of 6	NP_001333347.1	Q86UC2-2
	RSPH3	NR_144434.1		n.1340C>T		non_coding_transcript_exon	Exon 6 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.703C>T	p.Arg235Cys	missense	Exon 6 of 8	ENSP00000356036.1	A0A0C4DFU3
	RSPH3	ENST00000884885.1		c.535C>T	p.Arg179Cys	missense	Exon 5 of 7	ENSP00000554944.1
	RSPH3	ENST00000449822.6	TSL:2	c.415C>T	p.Arg139Cys	missense	Exon 4 of 6	ENSP00000393195.1	A0A0C4DG29

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251378 AF XY: 0.0000147

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111862

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

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
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Benign	0.27
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.62		Loss of ubiquitination at K379 (P = 0.1045)
MVP		0.40
MPC		1.1
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.45
gMVP		0.73
Mutation Taster		=72/28	polymorphism

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: rs778108869; hg19: chr6-159401962;