rs6927567

Variant names:

• chr6-116629571-G-A
• rs6927567
• NM_001010892.3:c.1667G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001010892.3(RSPH4A):​c.1667G>A​(p.Arg556His) variant causes a missense change. The variant allele was found at a frequency of 0.199 in 1,608,588 control chromosomes in the GnomAD database, including 33,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R556C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (2822 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30364 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.84
• Publications: 26 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

LOC124901386 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022907257).
• BP6: Variant 6-116629571-G-A is Benign according to our data. Variant chr6-116629571-G-A is described in ClinVar as Benign. ClinVar VariationId is 165060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.1667G>A	p.Arg556His	missense_variant	Exon 4 of 6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.1667G>A	p.Arg556His	missense_variant	Exon 4 of 6	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.1663-864G>A		intron_variant	Intron 3 of 4	1		ENSP00000357570.4
RSPH4A	ENST00000368580.4	c.926G>A	p.Arg309His	missense_variant	Exon 3 of 5	5		ENSP00000357569.4

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28334 AN: 151838 Hom.: 2819 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.214 AC: 53235 AN: 248496 AF XY: 0.214

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.300

Gnomad FIN exome AF: 0.258

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.200 AC: 291692 AN: 1456632 Hom.: 30364 Cov.: 31 AF XY: 0.201 AC XY: 145604 AN XY: 724974

African (AFR) AF: 0.116 AC: 3861 AN: 33396

American (AMR) AF: 0.214 AC: 9559 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 6171 AN: 26076

East Asian (EAS) AF: 0.320 AC: 12686 AN: 39634

South Asian (SAS) AF: 0.215 AC: 18544 AN: 86118

European-Finnish (FIN) AF: 0.257 AC: 13688 AN: 53240

Middle Eastern (MID) AF: 0.198 AC: 1141 AN: 5752

European-Non Finnish (NFE) AF: 0.193 AC: 213930 AN: 1107472

Other (OTH) AF: 0.201 AC: 12112 AN: 60228

GnomAD4 genome AF: 0.187 AC: 28347 AN: 151956 Hom.: 2822 Cov.: 32 AF XY: 0.190 AC XY: 14145 AN XY: 74254

African (AFR) AF: 0.121 AC: 4994 AN: 41436

American (AMR) AF: 0.202 AC: 3092 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 819 AN: 3468

East Asian (EAS) AF: 0.291 AC: 1498 AN: 5150

South Asian (SAS) AF: 0.216 AC: 1043 AN: 4824

European-Finnish (FIN) AF: 0.254 AC: 2677 AN: 10524

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13536 AN: 67958

Other (OTH) AF: 0.200 AC: 422 AN: 2114

Alfa AF: 0.200 Hom.: 14884

Bravo AF: 0.179

TwinsUK AF: 0.198 AC: 736

ALSPAC AF: 0.197 AC: 758

ESP6500AA AF: 0.120 AC: 529

ESP6500EA AF: 0.195 AC: 1679

ExAC AF: 0.213 AC: 25871

Asia WGS AF: 0.263 AC: 913 AN: 3478

EpiCase AF: 0.198

EpiControl AF: 0.202

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arg556His in exon 4 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 19.5% (1679/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs6927567). -

Apr 30, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

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

- -

Dec 01, 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. -

Primary ciliary dyskinesia 11 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Nov 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.085	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	3.9	H;.
PhyloP100		5.8
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.80	P;.
Vest4		0.90
MPC		0.70
ClinPred		0.095	T
GERP RS		5.2
Varity_R		0.77
gMVP		0.73
Mutation Taster		=56/44	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs6927567; hg19: chr6-116950734; COSMIC: COSV57635146;