6-158977771-C-T

Position:

chr6-158977771-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_031924.8(RSPH3):c.1024G>A(p.Glu342Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,614,090 control chromosomes in the GnomAD database, including 421 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 34 hom., cov: 32)

Exomes 𝑓: 0.022 ( 387 hom. )

Consequence

RSPH3
NM_031924.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.625

Variant links:

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 links:

RSPH3 (HGNC:):

RSPH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032161474).

BP6

Variant 6-158977771-C-T is Benign according to our data. Variant chr6-158977771-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-158977771-C-T is described in Lovd as [Likely_benign]. Variant chr6-158977771-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0178 (2718/152270) while in subpopulation NFE AF= 0.0238 (1616/68022). AF 95% confidence interval is 0.0228. There are 34 homozygotes in gnomad4. There are 1293 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH3	NM_031924.8 linkuse as main transcript	c.1024G>A	p.Glu342Lys	missense_variant	8/8	ENST00000367069.7	NP_114130.4	Q86UC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7 linkuse as main transcript	c.1024G>A	p.Glu342Lys	missense_variant	8/8	1	NM_031924.8	ENSP00000356036.1		A0A0C4DFU3
RSPH3	ENST00000449822.5 linkuse as main transcript	c.736G>A	p.Glu246Lys	missense_variant	6/6	2		ENSP00000393195.1		A0A0C4DG29

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2716

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00927

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0236

Gnomad ASJ

AF:

0.00664

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.0155

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0237

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0168

AC:

4213

AN:

251332

Hom.:

AF XY:

0.0171

AC XY:

2323

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0137

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.0230

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0217

AC:

31768

AN:

1461820

Hom.:

387

Cov.:

AF XY:

0.0213

AC XY:

15519

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0102

Gnomad4 AMR exome

AF:

0.0152

Gnomad4 ASJ exome

AF:

0.00746

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0127

Gnomad4 FIN exome

AF:

0.0155

Gnomad4 NFE exome

AF:

0.0246

Gnomad4 OTH exome

AF:

0.0187

GnomAD4 genome

AF:

0.0178

AC:

2718

AN:

152270

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

1293

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00929

Gnomad4 AMR

AF:

0.0236

Gnomad4 ASJ

AF:

0.00664

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00871

Gnomad4 FIN

AF:

0.0155

Gnomad4 NFE

AF:

0.0238

Gnomad4 OTH

AF:

0.0156

Alfa

AF:

0.0219

Hom.:

Bravo

AF:

0.0180

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0236

AC:

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.0245

AC:

211

ExAC

AF:

0.0167

AC:

2027

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0251

EpiControl

AF:

0.0241

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 32

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2024	See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.3

DANN

Benign

0.94

DEOGEN2

Benign

0.020

T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.49

T;T;T

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

.;.;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.017

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.052

.;.;B

Vest4

0.028

MPC

0.33

ClinPred

0.0022

GERP RS

-0.71

Varity_R

0.045

gMVP

0.16

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over