chr21-42476033-C-A

Variant names:

• chr21-42476033-C-A
• rs117385282
• NM_080860.4:c.742G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080860.4(RSPH1):​c.742G>T​(p.Gly248Trp) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G248R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.745
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 24

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20038927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.742G>T	p.Gly248Trp	missense_variant	Exon 8 of 9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.628G>T	p.Gly210Trp	missense_variant	Exon 7 of 8		NP_001273435.1
RSPH1	XM_011529786.2	c.670G>T	p.Gly224Trp	missense_variant	Exon 7 of 8		XP_011528088.1
RSPH1	XM_005261208.3	c.535G>T	p.Gly179Trp	missense_variant	Exon 6 of 7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.742G>T	p.Gly248Trp	missense_variant	Exon 8 of 9	1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3	c.628G>T	p.Gly210Trp	missense_variant	Exon 7 of 8	5		ENSP00000381395.3
RSPH1	ENST00000493019.1	n.2360G>T		non_coding_transcript_exon_variant	Exon 7 of 8	2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 7996

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		-0.74
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.10
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.97	D;.
Vest4		0.30
MutPred		0.35		Gain of catalytic residue at G248 (P = 0.0101);.;
MVP		0.36
MPC		0.47
ClinPred		0.84	D
GERP RS		-0.71
Varity_R		0.047
gMVP		0.23
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs117385282; hg19: chr21-43896143;