rs117169123

chr6-116628196-G-Achr6-116628196-G-C

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.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. 13/19 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:7
• Conservation: PhyloP100: 1.93

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=0.0052232444).
• BP6: Variant 6-116628196-G-A is Benign according to our data. Variant chr6-116628196-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116628196-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH4A	NM_001010892.3	c.1489G>A	p.Val497Ile	missense_variant	3/6	ENST00000229554.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH4A	ENST00000229554.10	c.1489G>A	p.Val497Ile	missense_variant	3/6	1	NM_001010892.3	P1
RSPH4A	ENST00000368581.8	c.1489G>A	p.Val497Ile	missense_variant	3/5	1
RSPH4A	ENST00000368580.4	c.922-1371G>A		intron_variant		5

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

GnomAD3 exomes AF: 0.0125 AC: 3131 AN: 250916 Hom.: 31 AF XY: 0.0133 AC XY: 1801 AN XY: 135640

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 SAS exome AF: 0.0132

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

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.00543

Gnomad4 EAS exome AF: 0.00179

Gnomad4 SAS exome AF: 0.0145

Gnomad4 FIN exome AF: 0.0246

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0135

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

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0248

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.0136 Hom.: 34

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -

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 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	This variant is associated with the following publications: (PMID: 31213628) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	RSPH4A: BP4, BS1, BS2 -

Primary ciliary dyskinesia 11 Benign:1

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. -

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
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
MutationTaster	Benign	0.68	D;D;D
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

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

Publications

LitVar

Other links and lift over

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