rs199715125

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_001346418.1(RSPH3):c.229G>A(p.Gly77Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,611,082 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G77G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

RSPH3
NM_001346418.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -4.13

Publications

2 publications found

Variant links:

Genes affected

RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

RSPH3 links:

TAGAP-AS1 (HGNC:55239): (TAGAP antisense RNA 1)

TAGAP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02807337).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000147 (215/1458910) while in subpopulation MID AF = 0.00139 (8/5750). AF 95% confidence interval is 0.000692. There are 1 homozygotes in GnomAdExome4. There are 113 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346418.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RSPH3	NM_031924.8	MANE Select	c.-198G>A		5_prime_UTR	Exon 1 of 8	NP_114130.4
RSPH3	NM_001346418.1		c.229G>A	p.Gly77Arg	missense	Exon 1 of 6	NP_001333347.1	Q86UC2-2
RSPH3	NR_144434.1		n.440G>A		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.-198G>A	5_prime_UTR	Exon 1 of 8	ENSP00000356036.1	A0A0C4DFU3
RSPH3	ENST00000884885.1		c.-198G>A	5_prime_UTR	Exon 1 of 7	ENSP00000554944.1
RSPH3	ENST00000449822.6	TSL:2	c.-198G>A	5_prime_UTR	Exon 1 of 6	ENSP00000393195.1	A0A0C4DG29

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000136

AC:

AN:

249198

AF XY:

0.000126

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000147

AC:

215

AN:

1458910

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

113

AN XY:

725288

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33440

American (AMR)

AF:

0.000516

AC:

AN:

44554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.00

AC:

AN:

86048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000141

AC:

157

AN:

1110004

Other (OTH)

AF:

0.000415

AC:

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000125

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41442

American (AMR)

AF:

0.000458

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.000150

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Primary ciliary dyskinesia 32 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.022

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.00072

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0055

LIST_S2

Benign

0.46

M_CAP

Benign

0.0019

MetaRNN

Benign

0.028

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-4.1

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.29

REVEL

Benign

0.020

Sift

Benign

0.83

Sift4G

Benign

0.84

Polyphen

0.0

Vest4

0.079

MutPred

0.15

Gain of methylation at G77 (P = 0.0328)

MVP

0.040

MPC

0.35

ClinPred

0.030

GERP RS

-9.3

PromoterAI

-0.17

Neutral

(source)

Varity_R

0.041

gMVP

0.018

Mutation Taster

=96/4

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