chr6-116622812-G-A

Variant names:

• chr6-116622812-G-A
• rs41289942
• NM_001010892.3:c.731G>A

Variant summary

Our verdict is Benign. The variant received -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:9
• Conservation: PhyloP100: 1.96
• Publications: 14 publications found

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]

RSPH4A Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 11

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.731G>A	p.Arg244His	missense_variant	Exon 2 of 6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.731G>A	p.Arg244His	missense_variant	Exon 2 of 6	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.731G>A	p.Arg244His	missense_variant	Exon 2 of 5	1		ENSP00000357570.4
RSPH4A	ENST00000368580.4	c.731G>A	p.Arg244His	missense_variant	Exon 2 of 5	5		ENSP00000357569.4

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

GnomAD2 exomes AF: 0.0200 AC: 5012 AN: 250896 AF XY: 0.0209

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 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

African (AFR) AF: 0.00299 AC: 100 AN: 33448

American (AMR) AF: 0.0222 AC: 995 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0486 AC: 1268 AN: 26108

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39650

South Asian (SAS) AF: 0.0224 AC: 1933 AN: 86206

European-Finnish (FIN) AF: 0.0103 AC: 548 AN: 53382

Middle Eastern (MID) AF: 0.0341 AC: 196 AN: 5752

European-Non Finnish (NFE) AF: 0.0212 AC: 23518 AN: 1110008

Other (OTH) AF: 0.0222 AC: 1336 AN: 60306

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

African (AFR) AF: 0.00364 AC: 151 AN: 41520

American (AMR) AF: 0.0204 AC: 312 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0224 AC: 108 AN: 4820

European-Finnish (FIN) AF: 0.00999 AC: 106 AN: 10608

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0227 AC: 1545 AN: 68014

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.0208 Hom.: 148

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RSPH4A: BP4, BS1, BS2 -

Feb 11, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31213628) -

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 11 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 12, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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
DEOGEN2	Benign	0.020	.;T;.
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
PhyloP100		2.0
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
Mutation Taster		=66/34	polymorphism (auto)

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

Other links and lift over

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