chr6-43670899-G-A

Position:

• chr6-43670899-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152732.5(RSPH9):​c.781G>A​(p.Val261Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0615 in 1,614,136 control chromosomes in the GnomAD database, including 4,504 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (440 hom., cov: 33)
  • Exomes 𝑓: 0.061 (4064 hom.)
• Consequence: RSPH9 NM_152732.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.07

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 (MetaRNN=9.112358E-4).
• BP6: Variant 6-43670899-G-A is Benign according to our data. Variant chr6-43670899-G-A is described in ClinVar as [Benign]. Clinvar id is 165065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43670899-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH9	NM_152732.5	c.781G>A	p.Val261Ile	missense_variant	5/5	ENST00000372163.5	NP_689945.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH9	ENST00000372163.5	c.781G>A	p.Val261Ile	missense_variant	5/5	1	NM_152732.5	ENSP00000361236.4
RSPH9	ENST00000372165.8	c.833G>A	p.Arg278His	missense_variant	6/6	2		ENSP00000361238.4

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10068 AN: 152204 Hom.: 443 Cov.: 33

Gnomad AFR AF: 0.0747

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0630

Gnomad ASJ AF: 0.0691

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.0307

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.0707

GnomAD3 exomes AF: 0.0766 AC: 19260 AN: 251432 Hom.: 1161 AF XY: 0.0801 AC XY: 10889 AN XY: 135894

Gnomad AFR exome AF: 0.0771

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.0706

Gnomad EAS exome AF: 0.190

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.0304

Gnomad NFE exome AF: 0.0514

Gnomad OTH exome AF: 0.0668

GnomAD4 exome AF: 0.0610 AC: 89175 AN: 1461814 Hom.: 4064 Cov.: 31 AF XY: 0.0642 AC XY: 46666 AN XY: 727212

Gnomad4 AFR exome AF: 0.0764

Gnomad4 AMR exome AF: 0.0583

Gnomad4 ASJ exome AF: 0.0706

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.0308

Gnomad4 NFE exome AF: 0.0482

Gnomad4 OTH exome AF: 0.0725

GnomAD4 genome AF: 0.0661 AC: 10074 AN: 152322 Hom.: 440 Cov.: 33 AF XY: 0.0673 AC XY: 5013 AN XY: 74484

Gnomad4 AFR AF: 0.0746

Gnomad4 AMR AF: 0.0630

Gnomad4 ASJ AF: 0.0691

Gnomad4 EAS AF: 0.208

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.0307

Gnomad4 NFE AF: 0.0501

Gnomad4 OTH AF: 0.0690

Alfa AF: 0.0570 Hom.: 390

Bravo AF: 0.0673

TwinsUK AF: 0.0510 AC: 189

ALSPAC AF: 0.0410 AC: 158

ESP6500AA AF: 0.0808 AC: 356

ESP6500EA AF: 0.0542 AC: 466

ExAC AF: 0.0796 AC: 9671

Asia WGS AF: 0.168 AC: 583 AN: 3478

EpiCase AF: 0.0558

EpiControl AF: 0.0581

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg278His in exon 6 of RSPH9: This variant is not expected to have clinical sign ificance because it has been identified in 8.1% (356/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs16896629). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 12, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2019

- -

Primary ciliary dyskinesia 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.77
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.00091	T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.036
Sift	Benign	0.61	T
Sift4G	Benign	0.26	T
Vest4		0.025
MPC		0.060
ClinPred		0.017	T
GERP RS		3.4
gMVP		0.12

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: rs16896629; hg19: chr6-43638636; COSMIC: COSV100928687; COSMIC: COSV100928687;