rs117169123

Variant names:

• chr6-116628196-G-A
• rs117169123
• NM_001010892.3:c.1489G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-116628196-G-A
• chr6-116628196-G-C

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.1489G>A​(p.Val497Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,614,050 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 32)
  • Exomes 𝑓: 0.015 (234 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.93
• Publications: 10 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=0.0052232444).
• BP6: Variant 6-116628196-G-A is Benign according to our data. Variant chr6-116628196-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178801.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 = 0.0115 (1745/152214) while in subpopulation NFE AF = 0.0165 (1124/67990). AF 95% confidence interval is 0.0157. There are 17 homozygotes in GnomAd4. There are 856 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.1489G>A	p.Val497Ile	missense_variant	Exon 3 of 6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.1489G>A	p.Val497Ile	missense_variant	Exon 3 of 6	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.1489G>A	p.Val497Ile	missense_variant	Exon 3 of 5	1		ENSP00000357570.4
RSPH4A	ENST00000368580.4	c.922-1371G>A		intron_variant	Intron 2 of 4	5		ENSP00000357569.4

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1743 AN: 152096 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0125 AC: 3131 AN: 250916 AF XY: 0.0133

Gnomad AFR exome AF: 0.00296

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0262

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0154 AC: 22443 AN: 1461836 Hom.: 234 Cov.: 32 AF XY: 0.0152 AC XY: 11051 AN XY: 727222

African (AFR) AF: 0.00236 AC: 79 AN: 33480

American (AMR) AF: 0.00371 AC: 166 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00543 AC: 142 AN: 26136

East Asian (EAS) AF: 0.00179 AC: 71 AN: 39698

South Asian (SAS) AF: 0.0145 AC: 1249 AN: 86258

European-Finnish (FIN) AF: 0.0246 AC: 1316 AN: 53398

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.0167 AC: 18563 AN: 1111980

Other (OTH) AF: 0.0135 AC: 816 AN: 60394

GnomAD4 genome AF: 0.0115 AC: 1745 AN: 152214 Hom.: 17 Cov.: 32 AF XY: 0.0115 AC XY: 856 AN XY: 74414

African (AFR) AF: 0.00349 AC: 145 AN: 41546

American (AMR) AF: 0.00562 AC: 86 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4820

European-Finnish (FIN) AF: 0.0248 AC: 263 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0165 AC: 1124 AN: 67990

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.0133 Hom.: 48

Bravo AF: 0.00910

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0123 AC: 1498

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0155

EpiControl AF: 0.0129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RSPH4A: BP4, BS1, BS2 -

Nov 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Val497Ile in exon 3 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 1.5% (133/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs117169123). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:2

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. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 11 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	12
DANN	Benign	0.77
DEOGEN2	Benign	0.0026	.;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.15	N;N
PhyloP100		1.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.11
Sift	Benign	0.67	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.84	P;B
Vest4		0.079
MPC		0.17
ClinPred		0.036	T
GERP RS		-2.5
Varity_R		0.028
gMVP		0.31
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs117169123; hg19: chr6-116949359; COSMIC: COSV99038036;