rs9488991

Positions:

• chr6-116630515-A-C

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.1879A>C​(p.Asn627His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0669 in 1,606,826 control chromosomes in the GnomAD database, including 6,293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N627K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1643 hom., cov: 31)
  • Exomes 𝑓: 0.062 (4650 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.22

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]

LOC124901386 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002024293).
• BP6: Variant 6-116630515-A-C is Benign according to our data. Variant chr6-116630515-A-C is described in ClinVar as [Benign]. Clinvar id is 165062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116630515-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH4A	NM_001010892.3	c.1879A>C	p.Asn627His	missense_variant	5/6	ENST00000229554.10
LOC124901386	XR_007059721.1	n.460-525T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH4A	ENST00000229554.10	c.1879A>C	p.Asn627His	missense_variant	5/6	1	NM_001010892.3	P1
RSPH4A	ENST00000368581.8	c.1743A>C	p.Pro581=	synonymous_variant	4/5	1
RSPH4A	ENST00000368580.4	c.1138A>C	p.Asn380His	missense_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17162 AN: 151826 Hom.: 1633 Cov.: 31

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.0224

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0992

GnomAD3 exomes AF: 0.0925 AC: 23267 AN: 251438 Hom.: 2007 AF XY: 0.0857 AC XY: 11640 AN XY: 135888

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.0192

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0463

Gnomad OTH exome AF: 0.0766

GnomAD4 exome AF: 0.0621 AC: 90341 AN: 1454882 Hom.: 4650 Cov.: 29 AF XY: 0.0623 AC XY: 45124 AN XY: 724174

Gnomad4 AFR exome AF: 0.251

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.0706

Gnomad4 EAS exome AF: 0.0241

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.0305

Gnomad4 NFE exome AF: 0.0477

Gnomad4 OTH exome AF: 0.0710

GnomAD4 genome AF: 0.113 AC: 17202 AN: 151944 Hom.: 1643 Cov.: 31 AF XY: 0.112 AC XY: 8332 AN XY: 74276

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.0225

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.0301

Gnomad4 NFE AF: 0.0457

Gnomad4 OTH AF: 0.0982

Alfa AF: 0.0616 Hom.: 1305

Bravo AF: 0.131

TwinsUK AF: 0.0572 AC: 212

ALSPAC AF: 0.0535 AC: 206

ESP6500AA AF: 0.227 AC: 999

ESP6500EA AF: 0.0521 AC: 448

ExAC AF: 0.0901 AC: 10933

Asia WGS AF: 0.0860 AC: 301 AN: 3478

EpiCase AF: 0.0463

EpiControl AF: 0.0487

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Asn627His in exon 5 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 22.7% (999/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs9488991). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 24, 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	- -

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

Feb 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	8.9e-9	P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.44
MPC		0.63
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.77
gMVP		0.79

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: rs9488991; hg19: chr6-116951678; COSMIC: COSV57634372;