chr6-158986384-C-T

Variant names:

• chr6-158986384-C-T
• rs41267751
• NM_031924.8:c.242G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031924.8(RSPH3):​c.242G>A​(p.Arg81Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,613,966 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R81W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (20 hom.)
• Consequence: RSPH3 NM_031924.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.962
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033236146).
• BP6: Variant 6-158986384-C-T is Benign according to our data. Variant chr6-158986384-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0071 (1081/152282) while in subpopulation AFR AF = 0.0193 (801/41556). AF 95% confidence interval is 0.0182. There are 9 homozygotes in GnomAd4. There are 487 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

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.242G>A	p.Arg81Gln	missense	Exon 3 of 8	NP_114130.4
	RSPH3	NM_001346418.1		c.631-3696G>A		intron	N/A	NP_001333347.1	Q86UC2-2
	RSPH3	NR_144434.1		n.879G>A		non_coding_transcript_exon	Exon 3 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.242G>A	p.Arg81Gln	missense	Exon 3 of 8	ENSP00000356036.1	A0A0C4DFU3
	RSPH3	ENST00000884885.1		c.242G>A	p.Arg81Gln	missense	Exon 3 of 7	ENSP00000554944.1
	RSPH3	ENST00000449822.6	TSL:2	c.205-3696G>A		intron	N/A	ENSP00000393195.1	A0A0C4DG29

Frequencies

GnomAD3 genomes AF: 0.00706 AC: 1074 AN: 152164 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00296 AC: 744 AN: 251362 AF XY: 0.00260

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00290 AC: 4242 AN: 1461684 Hom.: 20 Cov.: 30 AF XY: 0.00273 AC XY: 1987 AN XY: 727160

African (AFR) AF: 0.0181 AC: 604 AN: 33462

American (AMR) AF: 0.00170 AC: 76 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86250

European-Finnish (FIN) AF: 0.00109 AC: 58 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00290 AC: 3226 AN: 1111844

Other (OTH) AF: 0.00285 AC: 172 AN: 60392

GnomAD4 genome AF: 0.00710 AC: 1081 AN: 152282 Hom.: 9 Cov.: 32 AF XY: 0.00654 AC XY: 487 AN XY: 74458

African (AFR) AF: 0.0193 AC: 801 AN: 41556

American (AMR) AF: 0.00425 AC: 65 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00279 AC: 190 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00419 Hom.: 9

Bravo AF: 0.00761

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00375 AC: 455

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00196

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia 32 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.1
DANN	Benign	0.29
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.96
PrimateAI	Benign	0.21	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.030	B
Vest4		0.12
MVP		0.055
MPC		0.34
ClinPred		0.000027	T
GERP RS		3.3
Varity_R		0.021
gMVP		0.048
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs41267751; hg19: chr6-159407416;