rs59110261

Variant names:

• chr6-43645081-A-G
• rs59110261
• NM_152732.5:c.-18A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152732.5(RSPH9):​c.-18A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 1,606,496 control chromosomes in the GnomAD database, including 830 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (465 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (365 hom.)
• Consequence: RSPH9 NM_152732.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0780
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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 (BayesDel_noAF=-0.76).
• BP6: Variant 6-43645081-A-G is Benign according to our data. Variant chr6-43645081-A-G is described in ClinVar as Benign. ClinVar VariationId is 262684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH9	NM_152732.5	c.-18A>G		5_prime_UTR_variant	Exon 1 of 5	ENST00000372163.5	NP_689945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH9	ENST00000372163.5	c.-18A>G		5_prime_UTR_variant	Exon 1 of 5	1	NM_152732.5	ENSP00000361236.4
RSPH9	ENST00000372165.8	c.-18A>G		5_prime_UTR_variant	Exon 1 of 6	2		ENSP00000361238.4

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6331 AN: 152080 Hom.: 463 Cov.: 32

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0302

GnomAD2 exomes AF: 0.0107 AC: 2554 AN: 239164 AF XY: 0.00788

Gnomad AFR exome AF: 0.148

Gnomad AMR exome AF: 0.00838

Gnomad ASJ exome AF: 0.000912

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000529

Gnomad NFE exome AF: 0.000468

Gnomad OTH exome AF: 0.00453

GnomAD4 exome AF: 0.00423 AC: 6152 AN: 1454298 Hom.: 365 Cov.: 31 AF XY: 0.00369 AC XY: 2674 AN XY: 723850

African (AFR) AF: 0.143 AC: 4777 AN: 33430

American (AMR) AF: 0.00891 AC: 398 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86208

European-Finnish (FIN) AF: 0.0000208 AC: 1 AN: 48148

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5764

European-Non Finnish (NFE) AF: 0.000294 AC: 326 AN: 1110066

Other (OTH) AF: 0.00926 AC: 558 AN: 60244

GnomAD4 genome AF: 0.0417 AC: 6345 AN: 152198 Hom.: 465 Cov.: 32 AF XY: 0.0399 AC XY: 2970 AN XY: 74412

African (AFR) AF: 0.144 AC: 5984 AN: 41506

American (AMR) AF: 0.0154 AC: 236 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68002

Other (OTH) AF: 0.0299 AC: 63 AN: 2110

Alfa AF: 0.0172 Hom.: 65

Bravo AF: 0.0471

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Dec 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia 12 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.74
PhyloP100		0.078
PromoterAI		0.53	Over-expression
Mutation Taster		=300/0	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: rs59110261; hg19: chr6-43612818;