rs9488992

Positions:

• chr6-116632389-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001010892.3(RSPH4A):​c.2099C>T​(p.Ala700Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00522 in 1,613,762 control chromosomes in the GnomAD database, including 378 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (196 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (182 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.129

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017312765).
• BP6: Variant 6-116632389-C-T is Benign according to our data. Variant chr6-116632389-C-T is described in ClinVar as [Benign]. Clinvar id is 227055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.2099C>T	p.Ala700Val	missense_variant	6/6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.2099C>T	p.Ala700Val	missense_variant	6/6	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.*160C>T		3_prime_UTR_variant	5/5	1		ENSP00000357570.4
RSPH4A	ENST00000368580.4	c.1358C>T	p.Ala453Val	missense_variant	5/5	5		ENSP00000357569.4

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4173 AN: 151930 Hom.: 196 Cov.: 32

Gnomad AFR AF: 0.0940

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0245

GnomAD3 exomes AF: 0.00740 AC: 1859 AN: 251150 Hom.: 78 AF XY: 0.00552 AC XY: 749 AN XY: 135742

Gnomad AFR exome AF: 0.0931

Gnomad AMR exome AF: 0.00548

Gnomad ASJ exome AF: 0.00745

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00290 AC: 4236 AN: 1461714 Hom.: 182 Cov.: 31 AF XY: 0.00251 AC XY: 1826 AN XY: 727152

Gnomad4 AFR exome AF: 0.0919

Gnomad4 AMR exome AF: 0.00561

Gnomad4 ASJ exome AF: 0.00784

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.00636

GnomAD4 genome AF: 0.0275 AC: 4187 AN: 152048 Hom.: 196 Cov.: 32 AF XY: 0.0268 AC XY: 1991 AN XY: 74332

Gnomad4 AFR AF: 0.0940

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.00504 Hom.: 57

Bravo AF: 0.0306

ESP6500AA AF: 0.0935 AC: 412

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00907 AC: 1101

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	Ala700Val in exon 6 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 9.4% (412/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs9488992). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 05, 2015	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

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 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.024	D;D
Sift4G	Benign	0.12	T;T
Polyphen		0.52	P;.
Vest4		0.058
MVP		0.42
MPC		0.14
ClinPred		0.028	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.26

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: rs9488992; hg19: chr6-116953552;