rs35110984

Variant names:

• chr6-43650410-C-T
• rs35110984
• NM_152732.5:c.263C>T

Variant summary

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

The NM_152732.5(RSPH9):​c.263C>T​(p.Ala88Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,736 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00060 (6 hom.)
• Consequence: RSPH9 NM_152732.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.24
• Publications: 1 publications found

Genes affected

RSPH9 (HGNC:21057): (radial spoke head component 9) This gene encodes a protein thought to be a component of the radial spoke head in motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia 12. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jul 2010]

RSPH9 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 12

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, 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=0.007455826).
• BP6: Variant 6-43650410-C-T is Benign according to our data. Variant chr6-43650410-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241994.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 = 0.006 (914/152276) while in subpopulation AFR AF = 0.0209 (869/41554). AF 95% confidence interval is 0.0198. There are 11 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152732.5. 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
	RSPH9	NM_152732.5	MANE Select	c.263C>T	p.Ala88Val	missense	Exon 2 of 5	NP_689945.2
	RSPH9	NM_001424119.1		c.263C>T	p.Ala88Val	missense	Exon 2 of 6	NP_001411048.1
	RSPH9	NM_001193341.2		c.263C>T	p.Ala88Val	missense	Exon 2 of 6	NP_001180270.1	Q9H1X1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH9	ENST00000372163.5	TSL:1 MANE Select	c.263C>T	p.Ala88Val	missense	Exon 2 of 5	ENSP00000361236.4	Q9H1X1-1
	RSPH9	ENST00000372165.8	TSL:2	c.263C>T	p.Ala88Val	missense	Exon 2 of 6	ENSP00000361238.4	Q9H1X1-2
	RSPH9	ENST00000890744.1		c.263C>T	p.Ala88Val	missense	Exon 3 of 6	ENSP00000560803.1

Frequencies

GnomAD3 genomes AF: 0.00598 AC: 910 AN: 152158 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00141 AC: 355 AN: 251464 AF XY: 0.00104

Gnomad AFR exome AF: 0.0204

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000598 AC: 874 AN: 1461460 Hom.: 6 Cov.: 32 AF XY: 0.000519 AC XY: 377 AN XY: 727024

African (AFR) AF: 0.0229 AC: 766 AN: 33472

American (AMR) AF: 0.000447 AC: 20 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5494

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111958

Other (OTH) AF: 0.00123 AC: 74 AN: 60348

GnomAD4 genome AF: 0.00600 AC: 914 AN: 152276 Hom.: 11 Cov.: 31 AF XY: 0.00545 AC XY: 406 AN XY: 74440

African (AFR) AF: 0.0209 AC: 869 AN: 41554

American (AMR) AF: 0.00216 AC: 33 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00246 Hom.: 9

Bravo AF: 0.00657

ESP6500AA AF: 0.0161 AC: 71

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00178 AC: 216

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.067
Sift	Benign	0.46	T
Sift4G	Benign	0.11	T
Polyphen		0.033	B
Vest4		0.56
MVP		0.52
MPC		0.29
ClinPred		0.014	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.64
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs35110984; hg19: chr6-43618147;