chr6-116617069-C-G

Variant names:

• chr6-116617069-C-G
• rs13213314
• NM_001010892.3:c.446C>G

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.446C>G​(p.Thr149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,614,118 control chromosomes in the GnomAD database, including 10,134 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (662 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9472 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.617
• 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=0.0016322434).
• BP6: Variant 6-116617069-C-G is Benign according to our data. Variant chr6-116617069-C-G is described in ClinVar as Benign. ClinVar VariationId is 178799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.446C>G	p.Thr149Ser	missense_variant	Exon 1 of 6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.446C>G	p.Thr149Ser	missense_variant	Exon 1 of 6	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.446C>G	p.Thr149Ser	missense_variant	Exon 1 of 5	1		ENSP00000357570.4
RSPH4A	ENST00000368580.4	c.446C>G	p.Thr149Ser	missense_variant	Exon 1 of 5	5		ENSP00000357569.4

Frequencies

GnomAD3 genomes AF: 0.0784 AC: 11923 AN: 152150 Hom.: 662 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0776

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.0837

GnomAD2 exomes AF: 0.0803 AC: 20182 AN: 251352 AF XY: 0.0812

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.0517

Gnomad ASJ exome AF: 0.0788

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.0940

GnomAD4 exome AF: 0.108 AC: 157392 AN: 1461850 Hom.: 9472 Cov.: 33 AF XY: 0.106 AC XY: 76816 AN XY: 727224

African (AFR) AF: 0.0172 AC: 576 AN: 33478

American (AMR) AF: 0.0553 AC: 2475 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 1989 AN: 26136

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39700

South Asian (SAS) AF: 0.0325 AC: 2804 AN: 86258

European-Finnish (FIN) AF: 0.0907 AC: 4843 AN: 53420

Middle Eastern (MID) AF: 0.0874 AC: 504 AN: 5768

European-Non Finnish (NFE) AF: 0.124 AC: 138348 AN: 1111970

Other (OTH) AF: 0.0966 AC: 5837 AN: 60396

GnomAD4 genome AF: 0.0783 AC: 11921 AN: 152268 Hom.: 662 Cov.: 32 AF XY: 0.0743 AC XY: 5533 AN XY: 74472

African (AFR) AF: 0.0217 AC: 902 AN: 41560

American (AMR) AF: 0.0675 AC: 1033 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4828

European-Finnish (FIN) AF: 0.0776 AC: 824 AN: 10614

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8466 AN: 67994

Other (OTH) AF: 0.0829 AC: 175 AN: 2112

Alfa AF: 0.107 Hom.: 316

Bravo AF: 0.0755

TwinsUK AF: 0.116 AC: 430

ALSPAC AF: 0.130 AC: 501

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.123 AC: 1056

ExAC AF: 0.0814 AC: 9886

Asia WGS AF: 0.0200 AC: 73 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.120

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr149Ser in exon 1 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 12.3% (1056/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs13213314). -

Primary ciliary dyskinesia Benign:2

Dec 10, 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. -

Feb 03, 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 12, 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

Jan 13, 2019

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	Benign	0.078
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.24
DANN	Benign	0.46
DEOGEN2	Benign	0.0050	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.30	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L
PhyloP100		-0.62
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.60	N;N;N
REVEL	Benign	0.032
Sift	Benign	0.086	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.043
MutPred		0.042		Gain of phosphorylation at T149 (P = 0.0892);Gain of phosphorylation at T149 (P = 0.0892);Gain of phosphorylation at T149 (P = 0.0892);
MPC		0.13
ClinPred		0.0028	T
GERP RS		2.8
PromoterAI		0.057	Neutral
Varity_R		0.035
gMVP		0.065
Mutation Taster		=96/4	polymorphism (auto)

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: rs13213314; hg19: chr6-116938232; COSMIC: COSV57634685;