rs9488993

Variant names:

• chr6-116632877-A-C
• rs9488993
• NM_001010892.3:c.*436A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-116632877-A-C
• chr6-116632877-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001010892.3(RSPH4A):​c.*436A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0724 in 202,836 control chromosomes in the GnomAD database, including 836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.080 (705 hom., cov: 32)
  • Exomes 𝑓: 0.050 (131 hom.)
• Consequence: RSPH4A NM_001010892.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.376
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-116632877-A-C is Benign according to our data. Variant chr6-116632877-A-C is described in ClinVar as Benign. ClinVar VariationId is 355130.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.*436A>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.*436A>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.*648A>C		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000357570.4

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12144 AN: 152150 Hom.: 702 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.0545

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0802

GnomAD4 exome AF: 0.0499 AC: 2521 AN: 50568 Hom.: 131 Cov.: 0 AF XY: 0.0471 AC XY: 1255 AN XY: 26660

African (AFR) AF: 0.116 AC: 98 AN: 848

American (AMR) AF: 0.186 AC: 665 AN: 3568

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 47 AN: 1074

East Asian (EAS) AF: 0.0241 AC: 71 AN: 2946

South Asian (SAS) AF: 0.0466 AC: 324 AN: 6956

European-Finnish (FIN) AF: 0.0223 AC: 41 AN: 1838

Middle Eastern (MID) AF: 0.0294 AC: 5 AN: 170

European-Non Finnish (NFE) AF: 0.0371 AC: 1141 AN: 30736

Other (OTH) AF: 0.0530 AC: 129 AN: 2432

GnomAD4 genome AF: 0.0799 AC: 12161 AN: 152268 Hom.: 705 Cov.: 32 AF XY: 0.0792 AC XY: 5897 AN XY: 74462

African (AFR) AF: 0.135 AC: 5619 AN: 41540

American (AMR) AF: 0.159 AC: 2438 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 184 AN: 3470

East Asian (EAS) AF: 0.0210 AC: 109 AN: 5186

South Asian (SAS) AF: 0.0547 AC: 264 AN: 4826

European-Finnish (FIN) AF: 0.0300 AC: 318 AN: 10616

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0448 AC: 3045 AN: 68014

Other (OTH) AF: 0.0794 AC: 168 AN: 2116

Alfa AF: 0.0597 Hom.: 326

Bravo AF: 0.0958

Asia WGS AF: 0.0450 AC: 160 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 11 Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.52
PhyloP100		0.38
Mutation Taster		=100/0	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: rs9488993; hg19: chr6-116954040;