rs6925922

Positions:

• chr6-116632906-T-C
• chr6-116632906-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001010892.3(RSPH4A):​c.*465T>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 0.187 in 184,144 control chromosomes in the GnomAD database, including 3,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (2826 hom., cov: 32)
  • Exomes 𝑓: 0.19 (681 hom.)
• Consequence: RSPH4A NM_001010892.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.914

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-116632906-T-C is Benign according to our data. Variant chr6-116632906-T-C is described in ClinVar as [Benign]. Clinvar id is 355131.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH4A	NM_001010892.3	c.*465T>C		3_prime_UTR_variant	6/6	ENST00000229554.10
LOC124901386	XR_007059721.1	n.459+899A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH4A	ENST00000229554.10	c.*465T>C		3_prime_UTR_variant	6/6	1	NM_001010892.3	P1
RSPH4A	ENST00000368581.8	c.*677T>C		3_prime_UTR_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28347 AN: 152012 Hom.: 2823 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.200

GnomAD4 exome AF: 0.190 AC: 6069 AN: 32016 Hom.: 681 Cov.: 0 AF XY: 0.195 AC XY: 3282 AN XY: 16862

Gnomad4 AFR exome AF: 0.0893

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.286

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.203

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.186 AC: 28361 AN: 152128 Hom.: 2826 Cov.: 32 AF XY: 0.190 AC XY: 14136 AN XY: 74344

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.203

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.293

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.199

Gnomad4 OTH AF: 0.200

Alfa AF: 0.200 Hom.: 3054

Bravo AF: 0.179

Asia WGS AF: 0.266 AC: 925 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.36
DANN	Benign	0.65

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: rs6925922; hg19: chr6-116954069;