rs41267753

chr6-158986415-G-Achr6-158986415-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031924.8(RSPH3):c.211C>T(p.Arg71Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0288 in 1,609,950 control chromosomes in the GnomAD database, including 1,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.053 (380 hom., cov: 32)
  • Exomes 𝑓: 0.026 (801 hom.)
• Consequence: RSPH3 NM_031924.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.13

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002583176).
• BP6: Variant 6-158986415-G-A is Benign according to our data. Variant chr6-158986415-G-A is described in ClinVar as [Benign]. Clinvar id is 475835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH3	NM_031924.8	c.211C>T	p.Arg71Trp	missense_variant	3/8	ENST00000367069.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH3	ENST00000367069.7	c.211C>T	p.Arg71Trp	missense_variant	3/8	1	NM_031924.8	P1
RSPH3	ENST00000449822.5	c.205-3727C>T		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8113 AN: 152094 Hom.: 379 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0265

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0335

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0502

GnomAD3 exomes AF: 0.0293 AC: 7280 AN: 248750 Hom.: 212 AF XY: 0.0278 AC XY: 3746 AN XY: 134562

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.000384

Gnomad SAS exome AF: 0.0230

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0262 AC: 38206 AN: 1457738 Hom.: 801 Cov.: 30 AF XY: 0.0259 AC XY: 18788 AN XY: 725442

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.0162

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0227

Gnomad4 FIN exome AF: 0.0363

Gnomad4 NFE exome AF: 0.0241

Gnomad4 OTH exome AF: 0.0334

GnomAD4 genome AF: 0.0534 AC: 8132 AN: 152212 Hom.: 380 Cov.: 32 AF XY: 0.0512 AC XY: 3807 AN XY: 74420

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0264

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0335

Gnomad4 NFE AF: 0.0247

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0271 Hom.: 157

Bravo AF: 0.0561

TwinsUK AF: 0.0235 AC: 87

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.124 AC: 548

ESP6500EA AF: 0.0245 AC: 211

ExAC AF: 0.0325 AC: 3951

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.0246

EpiControl AF: 0.0240

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 32 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.57
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.034	T;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	.;D
Vest4		0.13
MPC		0.82
ClinPred		0.015	T
GERP RS		5.6
Varity_R		0.14
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs41267753; hg19: chr6-159407447;