chr6-158999542-T-C

Variant names:

• chr6-158999542-T-C
• rs10945587
• NM_031924.8:c.9A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_031924.8(RSPH3):​c.9A>G​(p.Ser3Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 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
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

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

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

Ensembl Transcripts

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

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

GnomAD2 exomes AF: 0.232 AC: 56530 AN: 243884 AF XY: 0.215

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 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

African (AFR) AF: 0.402 AC: 13317 AN: 33144

American (AMR) AF: 0.498 AC: 21781 AN: 43772

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3204 AN: 25486

East Asian (EAS) AF: 0.465 AC: 18287 AN: 39340

South Asian (SAS) AF: 0.208 AC: 17660 AN: 84836

European-Finnish (FIN) AF: 0.140 AC: 7414 AN: 52910

Middle Eastern (MID) AF: 0.181 AC: 1027 AN: 5682

European-Non Finnish (NFE) AF: 0.125 AC: 138187 AN: 1102054

Other (OTH) AF: 0.181 AC: 10763 AN: 59624

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

African (AFR) AF: 0.402 AC: 16596 AN: 41252

American (AMR) AF: 0.353 AC: 5370 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3454

East Asian (EAS) AF: 0.415 AC: 2124 AN: 5120

South Asian (SAS) AF: 0.226 AC: 1072 AN: 4740

European-Finnish (FIN) AF: 0.140 AC: 1480 AN: 10552

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8457 AN: 67702

Other (OTH) AF: 0.241 AC: 507 AN: 2102

Alfa AF: 0.160 Hom.: 1630

Bravo AF: 0.268

Asia WGS AF: 0.323 AC: 1121 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia 32 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.7
DANN	Benign	0.50
PhyloP100		-0.16
PromoterAI		0.046	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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