6-116632391-G-C

Position:

• chr6-116632391-G-C

Variant summary

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

The NM_001010892.3(RSPH4A):​c.2101G>C​(p.Glu701Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,613,992 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.77

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046696067).
• BP6: Variant 6-116632391-G-C is Benign according to our data. Variant chr6-116632391-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 355125.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.2101G>C	p.Glu701Gln	missense_variant	6/6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.2101G>C	p.Glu701Gln	missense_variant	6/6	1	NM_001010892.3	ENSP00000229554.5
RSPH4A	ENST00000368581.8	c.*162G>C		3_prime_UTR_variant	5/5	1		ENSP00000357570.4
RSPH4A	ENST00000368580.4	c.1360G>C	p.Glu454Gln	missense_variant	5/5	5		ENSP00000357569.4

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152150 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000406 AC: 102 AN: 251138 Hom.: 0 AF XY: 0.000258 AC XY: 35 AN XY: 135730

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62 AN XY: 727162

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152268 Hom.: 2 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74464

Gnomad4 AFR AF: 0.00505

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000788 Hom.: 0

Bravo AF: 0.00168

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000478 AC: 58

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 15, 2016	- -

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 07, 2016	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	- -

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. -

RSPH4A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.17
Sift	Benign	0.53	T;T
Sift4G	Uncertain	0.033	D;D
Polyphen		0.030	B;.
Vest4		0.069
MVP		0.53
MPC		0.14
ClinPred		0.029	T
GERP RS		0.11
Varity_R		0.13
gMVP		0.48

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: rs140660854; hg19: chr6-116953554;