rs41281830

Positions:

• chr6-43666530-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152732.5(RSPH9):​c.671-4259C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 1,522,248 control chromosomes in the GnomAD database, including 584 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (42 hom., cov: 32)
  • Exomes 𝑓: 0.026 (542 hom.)
• Consequence: RSPH9 NM_152732.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.01

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]

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

RSPH9 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 6-43666530-C-T is Benign according to our data. Variant chr6-43666530-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 165064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43666530-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0182 (2764/152248) while in subpopulation SAS AF= 0.033 (159/4822). AF 95% confidence interval is 0.0288. There are 42 homozygotes in gnomad4. There are 1265 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH9	NM_152732.5	c.671-4259C>T		intron_variant		ENST00000372163.5	NP_689945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH9	ENST00000372163.5	c.671-4259C>T		intron_variant		1	NM_152732.5	ENSP00000361236.4
RSPH9	ENST00000372165.8	c.722+10C>T		intron_variant		2		ENSP00000361238.4

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2765 AN: 152132 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0288

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0193 AC: 2802 AN: 145468 Hom.: 40 AF XY: 0.0202 AC XY: 1582 AN XY: 78424

Gnomad AFR exome AF: 0.00416

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.00197

Gnomad SAS exome AF: 0.0296

Gnomad FIN exome AF: 0.00383

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0262 AC: 35860 AN: 1370000 Hom.: 542 Cov.: 24 AF XY: 0.0262 AC XY: 17713 AN XY: 677188

Gnomad4 AFR exome AF: 0.00436

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.00893

Gnomad4 EAS exome AF: 0.000760

Gnomad4 SAS exome AF: 0.0287

Gnomad4 FIN exome AF: 0.00591

Gnomad4 NFE exome AF: 0.0294

Gnomad4 OTH exome AF: 0.0237

GnomAD4 genome AF: 0.0182 AC: 2764 AN: 152248 Hom.: 42 Cov.: 32 AF XY: 0.0170 AC XY: 1265 AN XY: 74442

Gnomad4 AFR AF: 0.00510

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0330

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.0288

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0226 Hom.: 18

Bravo AF: 0.0177

Asia WGS AF: 0.0260 AC: 91 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

722+10C>T in intron 5 of RSPH9: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 4.5% (8/178) of English and Scottish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs41281830). -

Primary ciliary dyskinesia 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.21
DANN	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs41281830; hg19: chr6-43634267;