dbSNP rs9488993: RSPH4A:c.*436A>C (chr6-116632877-A-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.376

Variant links:

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 links:

LOC124901386 (HGNC:):

LOC124901386 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 link	c.*436A>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000229554.10	NP_001010892.1	Q5TD94-1B3KTA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10 link	c.*436A>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_001010892.3	ENSP00000229554.5		Q5TD94-1
RSPH4A	ENST00000368581.8 link	c.*648A>C		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000357570.4		Q5TD94-3

Frequencies

GnomAD3 genomes

AF:

0.0798

AC:

12144

AN:

152150

Hom.:

702

Cov.:

show subpopulations

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.:

AF XY:

0.0471

AC XY:

1255

AN XY:

26660

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.186

Gnomad4 ASJ exome

AF:

0.0438

Gnomad4 EAS exome

AF:

0.0241

Gnomad4 SAS exome

AF:

0.0466

Gnomad4 FIN exome

AF:

0.0223

Gnomad4 NFE exome

AF:

0.0371

Gnomad4 OTH exome

AF:

0.0530

GnomAD4 genome

AF:

0.0799

AC:

12161

AN:

152268

Hom.:

705

Cov.:

AF XY:

0.0792

AC XY:

5897

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.135

Gnomad4 AMR

AF:

0.159

Gnomad4 ASJ

AF:

0.0530

Gnomad4 EAS

AF:

0.0210

Gnomad4 SAS

AF:

0.0547

Gnomad4 FIN

AF:

0.0300

Gnomad4 NFE

AF:

0.0448

Gnomad4 OTH

AF:

0.0794

Alfa

AF:

0.0565

Hom.:

225

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

LINK: link

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over