6-158982502-G-C

Variant names:

• chr6-158982502-G-C
• rs796052119
• NM_031924.8:c.679C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031924.8(RSPH3):​c.679C>G​(p.Arg227Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000354 in 1,414,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RSPH3 NM_031924.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.57
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH3	NM_031924.8	MANE Select	c.679C>G	p.Arg227Gly	missense	Exon 5 of 8	NP_114130.4
	RSPH3	NM_001346418.1		c.817C>G	p.Arg273Gly	missense	Exon 3 of 6	NP_001333347.1
	RSPH3	NR_144434.1		n.1316C>G		non_coding_transcript_exon	Exon 5 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.679C>G	p.Arg227Gly	missense	Exon 5 of 8	ENSP00000356036.1
	RSPH3	ENST00000449822.6	TSL:2	c.391C>G	p.Arg131Gly	missense	Exon 3 of 6	ENSP00000393195.1

Frequencies

GnomAD3 genomes AF: 0.00000876 AC: 1 AN: 114162 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000898

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000354 AC: 5 AN: 1414370 Hom.: 0 Cov.: 30 AF XY: 0.00000569 AC XY: 4 AN XY: 702872

⚠️ 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: 32302

American (AMR) AF: 0.00 AC: 0 AN: 42572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25010

East Asian (EAS) AF: 0.00 AC: 0 AN: 37894

South Asian (SAS) AF: 0.00 AC: 0 AN: 79296

European-Finnish (FIN) AF: 0.0000200 AC: 1 AN: 49920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1083664

Other (OTH) AF: 0.00 AC: 0 AN: 58202

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000876 AC: 1 AN: 114162 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 54940

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

African (AFR) AF: 0.00 AC: 0 AN: 29280

American (AMR) AF: 0.0000898 AC: 1 AN: 11130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 4076

South Asian (SAS) AF: 0.00 AC: 0 AN: 3466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53202

Other (OTH) AF: 0.00 AC: 0 AN: 1428

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.51		Loss of MoRF binding (P = 0.0373)
MVP		0.45
MPC		1.1
ClinPred		1.0	D
GERP RS		3.1
Varity_R		0.74
gMVP		0.69
Mutation Taster		=21/79	disease causing

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: rs796052119; hg19: chr6-159403534;