21-42477348-G-C

Position:

• chr21-42477348-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080860.4(RSPH1):​c.670C>G​(p.Leu224Val) 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: 34)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

Genes affected

RSPH1 (HGNC:12371): (radial spoke head component 1) This gene encodes a male meiotic metaphase chromosome-associated acidic protein. This gene is expressed in tissues with motile cilia or flagella, including the trachea, lungs, airway brushings, and testes. Mutations in this gene result in primary ciliary dyskinesia-24. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

RSPH1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1429309).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.670C>G	p.Leu224Val	missense_variant	7/9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.556C>G	p.Leu186Val	missense_variant	6/8		NP_001273435.1
RSPH1	XM_011529786.2	c.598C>G	p.Leu200Val	missense_variant	6/8		XP_011528088.1
RSPH1	XM_005261208.3	c.463C>G	p.Leu155Val	missense_variant	5/7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.670C>G	p.Leu224Val	missense_variant	7/9	1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3	c.556C>G	p.Leu186Val	missense_variant	6/8	5		ENSP00000381395.3
RSPH1	ENST00000493019.1	n.2288C>G		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 31, 2020

This sequence change replaces leucine with valine at codon 224 of the RSPH1 protein (p.Leu224Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RSPH1-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Benign	0.92
DEOGEN2	Benign	0.035	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.091
Sift	Benign	0.65	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.85	P;.
Vest4		0.26
MutPred		0.26		Gain of sheet (P = 0.039);.;
MVP		0.53
MPC		0.12
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.12
gMVP		0.21

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: rs375795708; hg19: chr21-43897458; COSMIC: COSV52320624;