chr6-158977601-T-C

Variant names:

• chr6-158977601-T-C
• rs3756988
• NM_031924.8:c.1194A>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.1194A>G​(p.Glu398Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,613,290 control chromosomes in the GnomAD database, including 20,472 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2047 hom., cov: 32)
  • Exomes 𝑓: 0.13 (18425 hom.)
• Consequence: RSPH3 NM_031924.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.86
• Publications: 26 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]

RSPH3 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 32

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-158977601-T-C is Benign according to our data. Variant chr6-158977601-T-C is described in ClinVar as Benign. ClinVar VariationId is 1170194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.86 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.1194A>G	p.Glu398Glu	synonymous	Exon 8 of 8	NP_114130.4
	RSPH3	NM_001346418.1		c.1332A>G	p.Glu444Glu	synonymous	Exon 6 of 6	NP_001333347.1	Q86UC2-2
	RSPH3	NR_144434.1		n.1831A>G		non_coding_transcript_exon	Exon 8 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.1194A>G	p.Glu398Glu	synonymous	Exon 8 of 8	ENSP00000356036.1	A0A0C4DFU3
	RSPH3	ENST00000884885.1		c.1026A>G	p.Glu342Glu	synonymous	Exon 7 of 7	ENSP00000554944.1
	RSPH3	ENST00000449822.6	TSL:2	c.906A>G	p.Glu302Glu	synonymous	Exon 6 of 6	ENSP00000393195.1	A0A0C4DG29

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20018 AN: 151974 Hom.: 2037 Cov.: 32

Gnomad AFR AF: 0.0842

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0995

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.188 AC: 47187 AN: 251182 AF XY: 0.177

Gnomad AFR exome AF: 0.0804

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.401

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.128 AC: 187577 AN: 1461198 Hom.: 18425 Cov.: 32 AF XY: 0.128 AC XY: 93397 AN XY: 726932

African (AFR) AF: 0.0791 AC: 2646 AN: 33470

American (AMR) AF: 0.471 AC: 21033 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2972 AN: 26122

East Asian (EAS) AF: 0.463 AC: 18351 AN: 39658

South Asian (SAS) AF: 0.186 AC: 16039 AN: 86220

European-Finnish (FIN) AF: 0.104 AC: 5541 AN: 53334

Middle Eastern (MID) AF: 0.131 AC: 754 AN: 5766

European-Non Finnish (NFE) AF: 0.101 AC: 112068 AN: 1111594

Other (OTH) AF: 0.135 AC: 8173 AN: 60370

GnomAD4 genome AF: 0.132 AC: 20067 AN: 152092 Hom.: 2047 Cov.: 32 AF XY: 0.137 AC XY: 10190 AN XY: 74336

African (AFR) AF: 0.0847 AC: 3516 AN: 41492

American (AMR) AF: 0.306 AC: 4672 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 399 AN: 3468

East Asian (EAS) AF: 0.414 AC: 2140 AN: 5164

South Asian (SAS) AF: 0.202 AC: 971 AN: 4804

European-Finnish (FIN) AF: 0.106 AC: 1127 AN: 10594

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0995 AC: 6764 AN: 67992

Other (OTH) AF: 0.146 AC: 308 AN: 2110

Alfa AF: 0.120 Hom.: 3244

Bravo AF: 0.151

Asia WGS AF: 0.287 AC: 998 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.105

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	-0.95
CADD	Benign	0.38
DANN	Benign	0.36
PhyloP100		-3.9
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: rs3756988; hg19: chr6-159398633; COSMIC: COSV51921510; COSMIC: COSV51921510;