chr6-43666530-C-T

Variant names:

• chr6-43666530-C-T
• rs41281830
• NM_152732.5:c.671-4259C>T

Variant summary

Our verdict is Benign. The variant received -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
• 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: ClinGen, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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=-0.95).
• BP6: Variant 6-43666530-C-T is Benign according to our data. Variant chr6-43666530-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 AR,AD gene

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.671-4259C>T		intron	N/A	NP_689945.2
	RSPH9	NM_001424119.1		c.767+10C>T		intron	N/A	NP_001411048.1
	RSPH9	NM_001193341.2		c.722+10C>T		intron	N/A	NP_001180270.1	Q9H1X1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH9	ENST00000372163.5	TSL:1 MANE Select	c.671-4259C>T		intron	N/A	ENSP00000361236.4	Q9H1X1-1
	RSPH9	ENST00000372165.8	TSL:2	c.722+10C>T		intron	N/A	ENSP00000361238.4	Q9H1X1-2
	RSPH9	ENST00000890744.1		c.671-4259C>T		intron	N/A	ENSP00000560803.1

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

GnomAD2 exomes AF: 0.0193 AC: 2802 AN: 145468 AF XY: 0.0202

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 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

African (AFR) AF: 0.00436 AC: 135 AN: 30962

American (AMR) AF: 0.0165 AC: 580 AN: 35134

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 221 AN: 24754

East Asian (EAS) AF: 0.000760 AC: 27 AN: 35526

South Asian (SAS) AF: 0.0287 AC: 2247 AN: 78276

European-Finnish (FIN) AF: 0.00591 AC: 284 AN: 48052

Middle Eastern (MID) AF: 0.00561 AC: 31 AN: 5528

European-Non Finnish (NFE) AF: 0.0294 AC: 30988 AN: 1054886

Other (OTH) AF: 0.0237 AC: 1347 AN: 56882

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

African (AFR) AF: 0.00510 AC: 212 AN: 41550

American (AMR) AF: 0.0186 AC: 285 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5178

South Asian (SAS) AF: 0.0330 AC: 159 AN: 4822

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0288 AC: 1962 AN: 68012

Other (OTH) AF: 0.0185 AC: 39 AN: 2108

Alfa AF: 0.0226 Hom.: 18

Bravo AF: 0.0177

Asia WGS AF: 0.0260 AC: 91 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.21
DANN	Benign	0.54
PhyloP100		-2.0
Mutation Taster		=100/0	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: rs41281830; hg19: chr6-43634267;