rs151107532

Variant names:

• chr21-42486463-T-G
• rs151107532
• NM_080860.4:c.275-2A>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_080860.4(RSPH1):​c.275-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000704 in 1,611,742 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003839055: This variant destroys a canonical splice acceptor site, is predicted to cause abnormal gene splicing, and has supporting functional evidence." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: RSPH1 NM_080860.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 6.80
• Publications: 14 publications found

Genes affected

RSPH1 (HGNC:12371): (radial spoke head component 1) This gene encodes a male meiotic metaphase chromosome-associated acidic protein. This gene is expressed in tissues with motile cilia or flagella, including the trachea, lungs, airway brushings, and testes. Mutations in this gene result in primary ciliary dyskinesia-24. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

RSPH1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 24

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV003839055: This variant destroys a canonical splice acceptor site, is predicted to cause abnormal gene splicing, and has supporting functional evidence.; SCV005878838: "functional studies show this variant leads to exon skipping and is associated with reduced protein expression" (Kott 2013, Onoufriadis 2014).; SCV000547685: Studies have shown that disruption of this splice site results in skipping of exons 4-5 or exons 4-6, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23993197, 24568568).; SCV004790655: In vitro RT-PCR analysis showed that the c.275-2A>C variant leads to the skipping of either exons 4-5 or exons 4-6, resulting in a frameshift and premature protein termination (Kott et al. 2013. PubMed ID: 23993197; Knowles et al. 2014. PubMed ID: 24568568).
• PP5: Variant 21-42486463-T-G is Pathogenic according to our data. Variant chr21-42486463-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 66990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080860.4. 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
	RSPH1	NM_080860.4	MANE Select	c.275-2A>C		splice_acceptor intron	N/A	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.161-2A>C		splice_acceptor intron	N/A	NP_001273435.1	Q8WYR4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	ENST00000291536.8	TSL:1 MANE Select	c.275-2A>C		splice_acceptor intron	N/A	ENSP00000291536.3	Q8WYR4-1
	RSPH1	ENST00000856519.1		c.275-2A>C		splice_acceptor intron	N/A	ENSP00000526578.1
	RSPH1	ENST00000398352.3	TSL:5	c.161-2A>C		splice_acceptor intron	N/A	ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000370 AC: 93 AN: 251452 AF XY: 0.000390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000712

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000732 AC: 1068 AN: 1459644 Hom.: 1 Cov.: 29 AF XY: 0.000688 AC XY: 500 AN XY: 726380

African (AFR) AF: 0.0000898 AC: 3 AN: 33410

American (AMR) AF: 0.000268 AC: 12 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000893 AC: 991 AN: 1110050

Other (OTH) AF: 0.000929 AC: 56 AN: 60296

GnomAD4 genome AF: 0.000441 AC: 67 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.000458 AC XY: 34 AN XY: 74302

African (AFR) AF: 0.0000483 AC: 2 AN: 41384

American (AMR) AF: 0.000720 AC: 11 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68030

Other (OTH) AF: 0.00191 AC: 4 AN: 2090

Alfa AF: 0.000595 Hom.: 0

Bravo AF: 0.000495

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Primary ciliary dyskinesia 24 (8)
3	-	-	not provided (3)
2	-	-	Primary ciliary dyskinesia (2)
1	-	-	RSPH1-related disorder (1)
-	-	-	Kartagener syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.8
GERP RS		5.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.84		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs151107532; hg19: chr21-43906573;