21-42477381-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_080860.4(RSPH1):c.637C>A(p.Gln213Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00088 in 1,612,602 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q213P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00089 ( 7 hom. )

Consequence

RSPH1
NM_080860.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.672

Publications

3 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004098326).

BP6

Variant 21-42477381-G-T is Benign according to our data. Variant chr21-42477381-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 241787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000889 (1300/1461756) while in subpopulation SAS AF = 0.00289 (249/86252). AF 95% confidence interval is 0.00259. There are 7 homozygotes in GnomAdExome4. There are 671 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD gene

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.637C>A	p.Gln213Lys	missense	Exon 7 of 9	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.523C>A	p.Gln175Lys	missense	Exon 6 of 8	NP_001273435.1	Q8WYR4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RSPH1	ENST00000291536.8	TSL:1 MANE Select	c.637C>A	p.Gln213Lys	missense	Exon 7 of 9	ENSP00000291536.3	Q8WYR4-1
RSPH1	ENST00000856519.1		c.565C>A	p.Gln189Lys	missense	Exon 6 of 8	ENSP00000526578.1
RSPH1	ENST00000398352.3	TSL:5	c.523C>A	p.Gln175Lys	missense	Exon 6 of 8	ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes

AF:

0.000790

AC:

119

AN:

150728

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000318

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00273

Gnomad FIN

AF:

0.00325

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000828

Gnomad OTH

AF:

0.000485

GnomAD2 exomes

AF:

0.000939

AC:

236

AN:

251414

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00254

Gnomad NFE exome

AF:

0.000660

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000889

AC:

1300

AN:

1461756

Hom.:

Cov.:

AF XY:

0.000923

AC XY:

671

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00289

AC:

249

AN:

86252

European-Finnish (FIN)

AF:

0.00251

AC:

134

AN:

53378

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000759

AC:

844

AN:

1111934

Other (OTH)

AF:

0.000944

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

128

193

257

321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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

AF:

0.000789

AC:

119

AN:

150846

Hom.:

Cov.:

AF XY:

0.000991

AC XY:

AN XY:

73680

show subpopulations

African (AFR)

AF:

0.000317

AC:

AN:

41026

American (AMR)

AF:

0.000132

AC:

AN:

15104

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00273

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.00325

AC:

AN:

10468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000828

AC:

AN:

67594

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.000649

Hom.:

Bravo

AF:

0.000404

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00124

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Primary ciliary dyskinesia (1)

RSPH1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.4

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.021

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0036

LIST_S2

Benign

0.0083

M_CAP

Benign

0.0073

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.4

PhyloP100

0.67

PrimateAI

Benign

0.43

PROVEAN

Benign

1.1

REVEL

Benign

0.069

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.090

MVP

0.19

MPC

0.12

ClinPred

0.0018

GERP RS

1.8

Varity_R

0.053

gMVP

0.34

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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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