rs10945587

chr6-158999542-T-Cchr6-158999542-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_031924.8(RSPH3):c.9A>G(p.Ser3=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,598,204 control chromosomes in the GnomAD database, including 31,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S3S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (5731 hom., cov: 31)
  • Exomes 𝑓: 0.16 (25597 hom.)
• Consequence: RSPH3 NM_031924.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.161

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]

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

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 6-158999542-T-C is Benign according to our data. Variant chr6-158999542-T-C is described in ClinVar as [Benign]. Clinvar id is 1165004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.161 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH3	NM_031924.8	c.9A>G	p.Ser3=	synonymous_variant	1/8	ENST00000367069.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH3	ENST00000367069.7	c.9A>G	p.Ser3=	synonymous_variant	1/8	1	NM_031924.8	P1
RSPH3	ENST00000449822.5	c.9A>G	p.Ser3=	synonymous_variant	1/6	2
TAGAP-AS1	ENST00000607391.5	n.236+8970T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36150 AN: 151238 Hom.: 5704 Cov.: 31

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.237

GnomAD3 exomes AF: 0.232 AC: 56530 AN: 243884 Hom.: 9627 AF XY: 0.215 AC XY: 28243 AN XY: 131498

Gnomad AFR exome AF: 0.404

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.403

Gnomad SAS exome AF: 0.210

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.160 AC: 231640 AN: 1446848 Hom.: 25597 Cov.: 32 AF XY: 0.159 AC XY: 113979 AN XY: 717354

Gnomad4 AFR exome AF: 0.402

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.465

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.140

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.239 AC: 36237 AN: 151356 Hom.: 5731 Cov.: 31 AF XY: 0.242 AC XY: 17905 AN XY: 73942

Gnomad4 AFR AF: 0.402

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.241

Alfa AF: 0.154 Hom.: 1341

Bravo AF: 0.268

Asia WGS AF: 0.323 AC: 1121 AN: 3478

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 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	5.7
Dann	Benign	0.50

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

Other links and lift over

dbSNP: rs10945587; hg19: chr6-159420574; COSMIC: COSV51921566; COSMIC: COSV51921566;