rs41289942

Positions:

• chr6-116622812-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001010892.3(RSPH4A):​c.731G>A​(p.Arg244His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,611,804 control chromosomes in the GnomAD database, including 432 homozygotes. In-silico tool predicts 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. R244C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (36 hom., cov: 33)
  • Exomes 𝑓: 0.020 (396 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.96

Genes affected

RSPH4A (HGNC:21558): (radial spoke head component 4A) This gene encodes a protein that appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein. Mutations in this gene cause primary ciliary dyskinesia 1, a disease arising from dysmotility of motile cilia and sperm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0094536245).
• BP6: Variant 6-116622812-G-A is Benign according to our data. Variant chr6-116622812-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 165059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2465/152224) while in subpopulation NFE AF= 0.0227 (1545/68014). AF 95% confidence interval is 0.0218. There are 36 homozygotes in gnomad4. There are 1155 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH4A	NM_001010892.3	c.731G>A	p.Arg244His	missense_variant	2/6	ENST00000229554.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH4A	ENST00000229554.10	c.731G>A	p.Arg244His	missense_variant	2/6	1	NM_001010892.3	P1
RSPH4A	ENST00000368581.8	c.731G>A	p.Arg244His	missense_variant	2/5	1
RSPH4A	ENST00000368580.4	c.731G>A	p.Arg244His	missense_variant	2/5	5

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2459 AN: 152106 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.00999

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.0200 AC: 5012 AN: 250896 Hom.: 65 AF XY: 0.0209 AC XY: 2837 AN XY: 135638

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0521

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0227

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0205 AC: 29901 AN: 1459580 Hom.: 396 Cov.: 30 AF XY: 0.0209 AC XY: 15188 AN XY: 726246

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0486

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.0224

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0212

Gnomad4 OTH exome AF: 0.0222

GnomAD4 genome AF: 0.0162 AC: 2465 AN: 152224 Hom.: 36 Cov.: 33 AF XY: 0.0155 AC XY: 1155 AN XY: 74440

Gnomad4 AFR AF: 0.00364

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.00999

Gnomad4 NFE AF: 0.0227

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0226 Hom.: 75

Bravo AF: 0.0164

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0233 AC: 200

ExAC AF: 0.0195 AC: 2367

Asia WGS AF: 0.00751 AC: 26 AN: 3476

EpiCase AF: 0.0261

EpiControl AF: 0.0271

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg244His in exon 2 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 2.3% (200/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs41289942). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 11 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 12, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RSPH4A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2020	This variant is associated with the following publications: (PMID: 31213628) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.0095	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.87	P;B;.
Vest4		0.17
MPC		0.29
ClinPred		0.039	T
GERP RS		4.8
Varity_R		0.52
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs41289942; hg19: chr6-116943975; COSMIC: COSV57634674;