chr6-43670899-G-A

Variant names:

• chr6-43670899-G-A
• rs16896629
• NM_152732.5:c.781G>A

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.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. 14/18 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
• Publications: 26 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 (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 VariationId is 165065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

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.781G>A	p.Val261Ile	missense	Exon 5 of 5	NP_689945.2
	RSPH9	NM_001424119.1		c.878G>A	p.Arg293His	missense	Exon 6 of 6	NP_001411048.1
	RSPH9	NM_001193341.2		c.833G>A	p.Arg278His	missense	Exon 6 of 6	NP_001180270.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH9	ENST00000372163.5	TSL:1 MANE Select	c.781G>A	p.Val261Ile	missense	Exon 5 of 5	ENSP00000361236.4
	RSPH9	ENST00000372165.8	TSL:2	c.833G>A	p.Arg278His	missense	Exon 6 of 6	ENSP00000361238.4
	RSPH9	ENST00000890744.1		c.781G>A	p.Val261Ile	missense	Exon 6 of 6	ENSP00000560803.1

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

GnomAD2 exomes AF: 0.0766 AC: 19260 AN: 251432 AF XY: 0.0801

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 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

African (AFR) AF: 0.0764 AC: 2558 AN: 33480

American (AMR) AF: 0.0583 AC: 2609 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 1844 AN: 26136

East Asian (EAS) AF: 0.218 AC: 8671 AN: 39700

South Asian (SAS) AF: 0.154 AC: 13278 AN: 86258

European-Finnish (FIN) AF: 0.0308 AC: 1647 AN: 53406

Middle Eastern (MID) AF: 0.0938 AC: 541 AN: 5768

European-Non Finnish (NFE) AF: 0.0482 AC: 53647 AN: 1111950

Other (OTH) AF: 0.0725 AC: 4380 AN: 60392

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

African (AFR) AF: 0.0746 AC: 3101 AN: 41576

American (AMR) AF: 0.0630 AC: 964 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 240 AN: 3472

East Asian (EAS) AF: 0.208 AC: 1075 AN: 5176

South Asian (SAS) AF: 0.160 AC: 771 AN: 4828

European-Finnish (FIN) AF: 0.0307 AC: 326 AN: 10620

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0501 AC: 3409 AN: 68022

Other (OTH) AF: 0.0690 AC: 146 AN: 2116

Alfa AF: 0.0584 Hom.: 561

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.1
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
Varity_R		0.041
gMVP		0.12
Mutation Taster		=94/6	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: rs16896629; hg19: chr6-43638636; COSMIC: COSV100928687; COSMIC: COSV100928687;