6-116629670-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001010892.3(RSPH4A):c.1766T>C(p.Leu589Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,608,076 control chromosomes in the GnomAD database, including 314,154 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (38064 hom., cov: 32)
  • Exomes 𝑓: 0.61 (276090 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.41

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.54601E-7).
• BP6: Variant 6-116629670-T-C is Benign according to our data. Variant chr6-116629670-T-C is described in ClinVar as [Benign]. Clinvar id is 165061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-116629670-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH4A	NM_001010892.3	c.1766T>C	p.Leu589Pro	missense_variant	4/6	ENST00000229554.10
LOC124901386	XR_007059721.1	n.780A>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH4A	ENST00000229554.10	c.1766T>C	p.Leu589Pro	missense_variant	4/6	1	NM_001010892.3	P1
RSPH4A	ENST00000368581.8	c.1663-765T>C		intron_variant		1
RSPH4A	ENST00000368580.4	c.1025T>C	p.Leu342Pro	missense_variant	3/5	5

Frequencies

GnomAD3 genomes AF: 0.691 AC: 105052 AN: 151974 Hom.: 37993 Cov.: 32

Gnomad AFR AF: 0.921

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.647

GnomAD3 exomes AF: 0.638 AC: 158674 AN: 248794 Hom.: 51849 AF XY: 0.635 AC XY: 85590 AN XY: 134706

Gnomad AFR exome AF: 0.927

Gnomad AMR exome AF: 0.657

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.504

Gnomad SAS exome AF: 0.745

Gnomad FIN exome AF: 0.616

Gnomad NFE exome AF: 0.594

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.612 AC: 890812 AN: 1455984 Hom.: 276090 Cov.: 36 AF XY: 0.614 AC XY: 444669 AN XY: 724616

Gnomad4 AFR exome AF: 0.930

Gnomad4 AMR exome AF: 0.660

Gnomad4 ASJ exome AF: 0.567

Gnomad4 EAS exome AF: 0.537

Gnomad4 SAS exome AF: 0.741

Gnomad4 FIN exome AF: 0.619

Gnomad4 NFE exome AF: 0.593

Gnomad4 OTH exome AF: 0.619

GnomAD4 genome AF: 0.692 AC: 105191 AN: 152092 Hom.: 38064 Cov.: 32 AF XY: 0.690 AC XY: 51310 AN XY: 74338

Gnomad4 AFR AF: 0.921

Gnomad4 AMR AF: 0.636

Gnomad4 ASJ AF: 0.570

Gnomad4 EAS AF: 0.508

Gnomad4 SAS AF: 0.738

Gnomad4 FIN AF: 0.621

Gnomad4 NFE AF: 0.596

Gnomad4 OTH AF: 0.651

Alfa AF: 0.617 Hom.: 38859

Bravo AF: 0.697

TwinsUK AF: 0.609 AC: 2259

ALSPAC AF: 0.601 AC: 2317

ESP6500AA AF: 0.905 AC: 3988

ESP6500EA AF: 0.593 AC: 5101

ExAC AF: 0.647 AC: 78520

Asia WGS AF: 0.674 AC: 2345 AN: 3478

EpiCase AF: 0.583

EpiControl AF: 0.580

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu589Pro in exon 4 of RSPH4A: This variant is not expected to have clinical sig nificance because it has been identified in 40.7% (3499/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs784133). -

Primary ciliary dyskinesia 11 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Benign	0.75
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.34	T;T
MetaRNN	Benign	5.5e-7	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.2	N;.
MutationTaster	Benign	0.19	P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	7.9	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.10
MPC		0.23
ClinPred		0.0049	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.38

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: rs784133; hg19: chr6-116950833; COSMIC: COSV57636986;