rs9488991

Variant names:

• chr6-116630515-A-C
• rs9488991
• NM_001010892.3:c.1879A>C

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.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 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
• Publications: 21 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

LOC124901386 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 165062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010892.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH4A	NM_001010892.3	MANE Select	c.1879A>C	p.Asn627His	missense	Exon 5 of 6	NP_001010892.1
	RSPH4A	NM_001161664.2		c.1743A>C	p.Pro581Pro	synonymous	Exon 4 of 5	NP_001155136.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH4A	ENST00000229554.10	TSL:1 MANE Select	c.1879A>C	p.Asn627His	missense	Exon 5 of 6	ENSP00000229554.5
	RSPH4A	ENST00000368581.8	TSL:1	c.1743A>C	p.Pro581Pro	synonymous	Exon 4 of 5	ENSP00000357570.4
	RSPH4A	ENST00000368580.4	TSL:5	c.1138A>C	p.Asn380His	missense	Exon 4 of 5	ENSP00000357569.4

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

GnomAD2 exomes AF: 0.0925 AC: 23267 AN: 251438 AF XY: 0.0857

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 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

African (AFR) AF: 0.251 AC: 8342 AN: 33228

American (AMR) AF: 0.233 AC: 10435 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 1843 AN: 26088

East Asian (EAS) AF: 0.0241 AC: 957 AN: 39652

South Asian (SAS) AF: 0.115 AC: 9894 AN: 86074

European-Finnish (FIN) AF: 0.0305 AC: 1629 AN: 53414

Middle Eastern (MID) AF: 0.0469 AC: 270 AN: 5754

European-Non Finnish (NFE) AF: 0.0477 AC: 52701 AN: 1105816

Other (OTH) AF: 0.0710 AC: 4270 AN: 60156

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

African (AFR) AF: 0.243 AC: 10062 AN: 41378

American (AMR) AF: 0.167 AC: 2552 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3470

East Asian (EAS) AF: 0.0225 AC: 116 AN: 5166

South Asian (SAS) AF: 0.120 AC: 576 AN: 4818

European-Finnish (FIN) AF: 0.0301 AC: 318 AN: 10570

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0457 AC: 3105 AN: 67982

Other (OTH) AF: 0.0982 AC: 207 AN: 2108

Alfa AF: 0.0688 Hom.: 3329

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia 11 (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
PhyloP100		7.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	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
Mutation Taster		=82/18	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: rs9488991; hg19: chr6-116951678; COSMIC: COSV57634372;