6-158977600-G-A

Position:

• chr6-158977600-G-A

Variant summary

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

The NM_031924.8(RSPH3):​c.1195C>T​(p.Leu399Phe) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RSPH3 NM_031924.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.977

Genes affected

RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

RSPH3 (HGNC:):

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=0.048620194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH3	NM_031924.8	c.1195C>T	p.Leu399Phe	missense_variant	8/8	ENST00000367069.7	NP_114130.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7	c.1195C>T	p.Leu399Phe	missense_variant	8/8	1	NM_031924.8	ENSP00000356036.1
RSPH3	ENST00000449822.5	c.907C>T	p.Leu303Phe	missense_variant	6/6	2		ENSP00000393195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2024

The c.1621C>T (p.L541F) alteration is located in exon 8 (coding exon 8) of the RSPH3 gene. This alteration results from a C to T substitution at nucleotide position 1621, causing the leucine (L) at amino acid position 541 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.056
DANN	Benign	0.42
DEOGEN2	Benign	0.010	T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.39	T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.46	.;.;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.43	N;N;N
REVEL	Benign	0.028
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.043
MutPred		0.16		.;.;Gain of loop (P = 0.1069);
MVP		0.030
MPC		0.32
ClinPred		0.069	T
GERP RS		-4.8
Varity_R		0.034
gMVP		0.011

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: chr6-159398632;