rs183372450

Positions:

• chr6-116628384-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001010892.3(RSPH4A):​c.1662+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,584,112 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: RSPH4A NM_001010892.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.98

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 6-116628384-C-T is Benign according to our data. Variant chr6-116628384-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227901.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.1662+15C>T		intron_variant		ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.1662+15C>T		intron_variant		1	NM_001010892.3	ENSP00000229554	P1
RSPH4A	ENST00000368581.8	c.1662+15C>T		intron_variant		1		ENSP00000357570
RSPH4A	ENST00000368580.4	c.922-1183C>T		intron_variant		5		ENSP00000357569

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00162 AC: 396 AN: 244194 Hom.: 4 AF XY: 0.00163 AC XY: 216 AN XY: 132660

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.000673

Gnomad ASJ exome AF: 0.00336

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000624

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00167 AC: 2395 AN: 1431890 Hom.: 8 Cov.: 25 AF XY: 0.00172 AC XY: 1226 AN XY: 714268

Gnomad4 AFR exome AF: 0.000274

Gnomad4 AMR exome AF: 0.000652

Gnomad4 ASJ exome AF: 0.00331

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000736

Gnomad4 FIN exome AF: 0.00239

Gnomad4 NFE exome AF: 0.00181

Gnomad4 OTH exome AF: 0.00173

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74422

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00226 Hom.: 0

Bravo AF: 0.00124

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 11 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 29, 2016

c.1662+15C>T in intron 3 of RSPH4A: This variant is not expected to have clinica l significance because it is not located within the splice consensus sequence. I t has been identified in 0.2% (164/65466) of European chromosomes, including 2 h omozygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs183372450). -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.013
DANN	Benign	0.18

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: rs183372450; hg19: chr6-116949547;