6-158977803-T-G

Position:

chr6-158977803-T-G

Variant summary

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

The ENST00000367069.7(RSPH3):c.992A>C(p.His331Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,614,150 control chromosomes in the GnomAD database, including 40 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H331R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0082 ( 22 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 18 hom. )

Consequence

RSPH3
ENST00000367069.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.82

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:

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=0.003074646).

BP6

Variant 6-158977803-T-G is Benign according to our data. Variant chr6-158977803-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 475823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0082 (1249/152330) while in subpopulation AFR AF= 0.0284 (1180/41572). AF 95% confidence interval is 0.027. There are 22 homozygotes in gnomad4. There are 629 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH3	NM_031924.8 linkuse as main transcript	c.992A>C	p.His331Pro	missense_variant	8/8	ENST00000367069.7	NP_114130.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7 linkuse as main transcript	c.992A>C	p.His331Pro	missense_variant	8/8	1	NM_031924.8	ENSP00000356036	P1
RSPH3	ENST00000449822.5 linkuse as main transcript	c.704A>C	p.His235Pro	missense_variant	6/6	2		ENSP00000393195

Frequencies

GnomAD3 genomes

AF:

0.00819

AC:

1247

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0284

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

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:

0.0000735

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00232

AC:

581

AN:

250852

Hom.:

AF XY:

0.00164

AC XY:

222

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.0318

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000883

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000830

AC:

1213

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000719

AC XY:

523

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0296

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.00172

GnomAD4 genome

AF:

0.00820

AC:

1249

AN:

152330

Hom.:

Cov.:

AF XY:

0.00844

AC XY:

629

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0284

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.00957

ESP6500AA

AF:

0.0340

AC:

150

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00288

AC:

350

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

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	Nov 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 15, 2023	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

RSPH3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0030

DANN

Benign

0.24

DEOGEN2

Benign

0.027

T;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.40

T;T;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

.;.;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.018

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.22

T;T;T

Polyphen

0.0010

.;.;B

Vest4

0.13

MVP

0.067

MPC

0.46

ClinPred

0.0038

GERP RS

-5.3

Varity_R

0.097

gMVP

0.39

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