chr6-116616726-T-C

Position:

• chr6-116616726-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000229554.10(RSPH4A):​c.103T>C​(p.Ser35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S35Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RSPH4A ENST00000229554.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.253

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022091836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH4A	NM_001010892.3	c.103T>C	p.Ser35Pro	missense_variant	1/6	ENST00000229554.10	NP_001010892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH4A	ENST00000229554.10	c.103T>C	p.Ser35Pro	missense_variant	1/6	1	NM_001010892.3	ENSP00000229554	P1
RSPH4A	ENST00000368581.8	c.103T>C	p.Ser35Pro	missense_variant	1/5	1		ENSP00000357570
RSPH4A	ENST00000368580.4	c.103T>C	p.Ser35Pro	missense_variant	1/5	5		ENSP00000357569

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.103T>C p.Ser35Pro variant in RSPH4A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser35Pro variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Ser35Pro in RSPH4A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 35 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.3
DANN	Benign	0.62
DEOGEN2	Benign	0.00072	.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.65	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.31	N;N;N
REVEL	Benign	0.022
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.046
MutPred		0.23		Loss of phosphorylation at S35 (P = 0.0018);Loss of phosphorylation at S35 (P = 0.0018);Loss of phosphorylation at S35 (P = 0.0018);
MVP		0.18
MPC		0.18
ClinPred		0.051	T
GERP RS		1.9
Varity_R		0.063
gMVP		0.055

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-116937889;