Genetic Variant RSPH3:p.Ser3Ser (chr6-158999542-T-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_031924.8(RSPH3):c.9A>C(p.Ser3Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,598,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S3S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RSPH3
NM_031924.8 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.161

Publications

13 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 links:

TAGAP-AS1 (HGNC:55239): (TAGAP antisense RNA 1)

TAGAP-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 6-158999542-T-G is Benign according to our data. Variant chr6-158999542-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 542474.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.161 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031924.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RSPH3	NM_031924.8	MANE Select	c.9A>C	p.Ser3Ser	synonymous	Exon 1 of 8	NP_114130.4
RSPH3	NM_001346418.1		c.435A>C	p.Ser145Ser	synonymous	Exon 1 of 6	NP_001333347.1	Q86UC2-2
RSPH3	NR_144434.1		n.646A>C		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.9A>C	p.Ser3Ser	synonymous	Exon 1 of 8	ENSP00000356036.1	A0A0C4DFU3
RSPH3	ENST00000884885.1		c.9A>C	p.Ser3Ser	synonymous	Exon 1 of 7	ENSP00000554944.1
RSPH3	ENST00000449822.6	TSL:2	c.9A>C	p.Ser3Ser	synonymous	Exon 1 of 6	ENSP00000393195.1	A0A0C4DG29

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151318

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000410

AC:

AN:

243884

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717550

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33162

American (AMR)

AF:

0.00

AC:

AN:

43820

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25494

East Asian (EAS)

AF:

0.00

AC:

AN:

39370

South Asian (SAS)

AF:

0.00

AC:

AN:

84878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102212

Other (OTH)

AF:

0.00

AC:

AN:

59644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151318

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41168

American (AMR)

AF:

0.00

AC:

AN:

15224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67722

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1630

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia 32 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

5.3

(source)

DANN

Benign

0.49

PhyloP100

-0.16

PromoterAI

0.088

Neutral

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over