rs575857124

Variant names:

• chr6-116632449-A-G
• rs575857124
• NM_001010892.3:c.*8A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001010892.3(RSPH4A):​c.*8A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,606,566 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00084 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (79 hom.)
• Consequence: RSPH4A NM_001010892.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.40
• Publications: 1 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 (BayesDel_noAF=-0.56).
• BP6: Variant 6-116632449-A-G is Benign according to our data. Variant chr6-116632449-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00084 (128/152308) while in subpopulation SAS AF = 0.0259 (125/4828). AF 95% confidence interval is 0.0222. There are 2 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.*8A>G		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.*8A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.*220A>G		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000357570.4
RSPH4A	ENST00000368580.4	c.*8A>G		downstream_gene_variant		5		ENSP00000357569.4

Frequencies

GnomAD3 genomes AF: 0.000834 AC: 127 AN: 152190 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00351 AC: 829 AN: 236254 AF XY: 0.00487

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000571

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000189

Gnomad OTH exome AF: 0.000687

GnomAD4 exome AF: 0.00170 AC: 2474 AN: 1454258 Hom.: 79 Cov.: 31 AF XY: 0.00253 AC XY: 1830 AN XY: 722490

African (AFR) AF: 0.0000599 AC: 2 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 43596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39604

South Asian (SAS) AF: 0.0279 AC: 2362 AN: 84658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53030

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5748

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1108136

Other (OTH) AF: 0.00146 AC: 88 AN: 60184

GnomAD4 genome AF: 0.000840 AC: 128 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0259 AC: 125 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68046

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.000106

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.*8A>G in RSPH4A: This variant is not expected to have clinical significance be cause it has been identified in 3% (404/12030) of South Asian chromosomes, inclu ding 7 homozygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs575857124). -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 11 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 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
BayesDel_noAF	Benign	-0.56
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		1.4
Mutation Taster		=99/1	polymorphism

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: rs575857124; hg19: chr6-116953612;