chr21-42477291-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_080860.4(RSPH1):c.727A>G(p.Ser243Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,338,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RSPH1
NM_080860.4 missense, splice_region

Scores

Splicing: ADA: 0.00005386

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.394

Publications

4 publications found

Variant links:

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: ClinGen, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RSPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013324052).

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.727A>G	p.Ser243Gly	missense splice_region	Exon 7 of 9	NP_543136.1
	RSPH1	NM_001286506.2		c.613A>G	p.Ser205Gly	missense splice_region	Exon 6 of 8	NP_001273435.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RSPH1	ENST00000291536.8	TSL:1 MANE Select	c.727A>G	p.Ser243Gly	missense splice_region	Exon 7 of 9	ENSP00000291536.3
RSPH1	ENST00000856519.1		c.655A>G	p.Ser219Gly	missense splice_region	Exon 6 of 8	ENSP00000526578.1
RSPH1	ENST00000398352.3	TSL:5	c.613A>G	p.Ser205Gly	missense splice_region	Exon 6 of 8	ENSP00000381395.3

Frequencies

GnomAD3 genomes

AF:

0.000319

AC:

AN:

112854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000156

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000256

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000859

Gnomad FIN

AF:

0.000305

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000438

Gnomad OTH

AF:

0.000627

GnomAD2 exomes

AF:

0.000395

AC:

AN:

245584

AF XY:

0.000421

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000353

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000571

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000560

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.000224

AC:

300

AN:

1338602

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

149

AN XY:

665472

show subpopulations

African (AFR)

AF:

0.0000991

AC:

AN:

30260

American (AMR)

AF:

0.000190

AC:

AN:

42084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22600

East Asian (EAS)

AF:

0.000108

AC:

AN:

27656

South Asian (SAS)

AF:

0.000191

AC:

AN:

83562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5310

European-Non Finnish (NFE)

AF:

0.000252

AC:

260

AN:

1032178

Other (OTH)

AF:

0.000190

AC:

AN:

52748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000319

AC:

AN:

112966

Hom.:

Cov.:

AF XY:

0.000329

AC XY:

AN XY:

54714

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000155

AC:

AN:

32192

American (AMR)

AF:

0.000256

AC:

AN:

11732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2734

East Asian (EAS)

AF:

0.00

AC:

AN:

3354

South Asian (SAS)

AF:

0.000860

AC:

AN:

3490

European-Finnish (FIN)

AF:

0.000305

AC:

AN:

6560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.000438

AC:

AN:

50240

Other (OTH)

AF:

0.000617

AC:

AN:

1620

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000400235), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.319

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000452

Hom.:

ExAC

AF:

0.000437

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Primary ciliary dyskinesia (1)

Primary ciliary dyskinesia 24 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.68

CADD

Benign

3.3

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.017

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00075

LIST_S2

Benign

0.46

M_CAP

Benign

0.0045

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.1

PhyloP100

0.39

PrimateAI

Benign

0.41

PROVEAN

Benign

0.28

REVEL

Benign

0.079

Sift

Benign

1.0

Sift4G

Benign

0.64

Polyphen

0.0

Vest4

0.098

MVP

0.048

MPC

0.087

ClinPred

0.0040

GERP RS

0.88

Varity_R

0.028

gMVP

0.11

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000054

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over