6-158986323-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_031924.8(RSPH3):c.303A>G(p.Thr101Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,614,006 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts 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 ( 381 hom. )

Consequence

RSPH3
NM_031924.8 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -4.49

Publications

6 publications found

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 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

RSPH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 6-158986323-T-C is Benign according to our data. Variant chr6-158986323-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-4.49 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0178 (2710/152270) while in subpopulation NFE AF = 0.0237 (1612/68014). AF 95% confidence interval is 0.0227. There are 34 homozygotes in GnomAd4. There are 1291 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH3	NM_031924.8 link	c.303A>G	p.Thr101Thr	synonymous_variant	Exon 3 of 8	ENST00000367069.7	NP_114130.4	Q86UC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7 link	c.303A>G	p.Thr101Thr	synonymous_variant	Exon 3 of 8	1	NM_031924.8	ENSP00000356036.1		A0A0C4DFU3
RSPH3	ENST00000449822.6 link	c.205-3635A>G		intron_variant	Intron 2 of 5	2		ENSP00000393195.1		A0A0C4DG29

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2708

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00922

Gnomad AMI

AF:

0.0945

Gnomad AMR

AF:

0.0236

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00869

Gnomad FIN

AF:

0.0154

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0237

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0167

AC:

4197

AN:

251402

AF XY:

0.0170

show subpopulations

Gnomad AFR exome

AF:

0.00880

Gnomad AMR exome

AF:

0.0145

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0164

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0169

GnomAD4 exome

AF:

0.0216

AC:

31566

AN:

1461736

Hom.:

381

Cov.:

AF XY:

0.0212

AC XY:

15431

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0101

AC:

339

AN:

33476

American (AMR)

AF:

0.0152

AC:

679

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00746

AC:

195

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0127

AC:

1092

AN:

86248

European-Finnish (FIN)

AF:

0.0155

AC:

830

AN:

53420

Middle Eastern (MID)

AF:

0.0248

AC:

143

AN:

5766

European-Non Finnish (NFE)

AF:

0.0244

AC:

27155

AN:

1111880

Other (OTH)

AF:

0.0187

AC:

1128

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

1564

3129

4693

6258

7822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1014

2028

3042

4056

5070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0178

AC:

2710

AN:

152270

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1291

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00924

AC:

384

AN:

41558

American (AMR)

AF:

0.0235

AC:

360

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00870

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0154

AC:

163

AN:

10604

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0237

AC:

1612

AN:

68014

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

131

263

394

526

657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0172

Hom.:

Bravo

AF:

0.0179

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0249

EpiControl

AF:

0.0240

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

Nov 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 13, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.089

(source)

DANN

Benign

0.55

PhyloP100

-4.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over