rs151158140

Positions:

chr21-42476042-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_080860.4(RSPH1):c.733G>A(p.Gly245Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,613,710 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 1 hom., cov: 30)

Exomes 𝑓: 0.0058 ( 31 hom. )

Consequence

RSPH1
NM_080860.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.462

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005465418).

BP6

Variant 21-42476042-C-T is Benign according to our data. Variant chr21-42476042-C-T is described in ClinVar as [Benign]. Clinvar id is 241791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42476042-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00449 (683/151968) while in subpopulation AMR AF= 0.0113 (173/15272). AF 95% confidence interval is 0.00995. There are 1 homozygotes in gnomad4. There are 304 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RSPH1	NM_080860.4 linkuse as main transcript	c.733G>A	p.Gly245Arg	missense_variant	8/9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2 linkuse as main transcript	c.619G>A	p.Gly207Arg	missense_variant	7/8		NP_001273435.1
RSPH1	XM_011529786.2 linkuse as main transcript	c.661G>A	p.Gly221Arg	missense_variant	7/8		XP_011528088.1
RSPH1	XM_005261208.3 linkuse as main transcript	c.526G>A	p.Gly176Arg	missense_variant	6/7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8 linkuse as main transcript	c.733G>A	p.Gly245Arg	missense_variant	8/9	1	NM_080860.4	ENSP00000291536	P1	Q8WYR4-1
RSPH1	ENST00000398352.3 linkuse as main transcript	c.619G>A	p.Gly207Arg	missense_variant	7/8	5		ENSP00000381395		Q8WYR4-2
RSPH1	ENST00000493019.1 linkuse as main transcript	n.2351G>A		non_coding_transcript_exon_variant	7/8	2

Frequencies

GnomAD3 genomes

AF:

0.00450

AC:

683

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00208

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00586

Gnomad OTH

AF:

0.00433

GnomAD3 exomes

AF:

0.00385

AC:

967

AN:

251258

Hom.:

AF XY:

0.00378

AC XY:

513

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00530

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00605

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00583

AC:

8524

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00567

AC XY:

4122

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00131

Gnomad4 AMR exome

AF:

0.00492

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00266

Gnomad4 NFE exome

AF:

0.00704

Gnomad4 OTH exome

AF:

0.00474

GnomAD4 genome

AF:

0.00449

AC:

683

AN:

151968

Hom.:

Cov.:

AF XY:

0.00409

AC XY:

304

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.0113

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00208

Gnomad4 NFE

AF:

0.00586

Gnomad4 OTH

AF:

0.00429

Alfa

AF:

0.00539

Hom.:

Bravo

AF:

0.00487

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.00343

AC:

416

EpiCase

AF:

0.00469

EpiControl

AF:

0.00587

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.0055

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.013

D;D

Sift4G

Benign

0.082

T;T

Polyphen

0.92

P;.

Vest4

0.33

MutPred

0.32

Gain of loop (P = 0.0045);.;

MVP

0.34

MPC

0.32

ClinPred

0.015

GERP RS

1.5

Varity_R

0.082

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over