6-43650520-G-A

Variant names:

• chr6-43650520-G-A
• rs199874020
• NM_152732.5:c.373G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001424119.1(RSPH9):​c.373G>A​(p.Val125Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V125L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RSPH9 NM_001424119.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0450
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058048815).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001424119.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH9	NM_152732.5	MANE Select	c.373G>A	p.Val125Ile	missense	Exon 2 of 5	NP_689945.2
	RSPH9	NM_001424119.1		c.373G>A	p.Val125Ile	missense	Exon 2 of 6	NP_001411048.1
	RSPH9	NM_001193341.2		c.373G>A	p.Val125Ile	missense	Exon 2 of 6	NP_001180270.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH9	ENST00000372163.5	TSL:1 MANE Select	c.373G>A	p.Val125Ile	missense	Exon 2 of 5	ENSP00000361236.4
	RSPH9	ENST00000372165.8	TSL:2	c.373G>A	p.Val125Ile	missense	Exon 2 of 6	ENSP00000361238.4
	RSPH9	ENST00000890744.1		c.373G>A	p.Val125Ile	missense	Exon 3 of 6	ENSP00000560803.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251488 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.26	N
PhyloP100		0.045
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.015
Sift	Benign	0.20	T
Sift4G	Benign	0.38	T
Polyphen		0.093	B
Vest4		0.23
MutPred		0.31		Loss of sheet (P = 0.0357)
MVP		0.61
MPC		0.18
ClinPred		0.12	T
GERP RS		0.97
Varity_R		0.026
gMVP		0.18
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199874020; hg19: chr6-43618257;