6-158986384-C-A

Position:

• chr6-158986384-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000367069.7(RSPH3):​c.242G>T​(p.Arg81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R81Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RSPH3 ENST00000367069.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.962

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16142249).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH3	NM_031924.8	c.242G>T	p.Arg81Leu	missense_variant	3/8	ENST00000367069.7	NP_114130.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7	c.242G>T	p.Arg81Leu	missense_variant	3/8	1	NM_031924.8	ENSP00000356036	P1
RSPH3	ENST00000449822.5	c.205-3696G>T		intron_variant		2		ENSP00000393195

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461702 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.075	T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Benign	0.074
Sift	Benign	0.054	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.57	.;P
Vest4		0.21
MutPred		0.50		.;Gain of helix (P = 0.0128);
MVP		0.16
MPC		0.58
ClinPred		0.86	D
GERP RS		3.3
Varity_R		0.099
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41267751; hg19: chr6-159407416; COSMIC: COSV99396291; COSMIC: COSV99396291;