21-42472829-G-A

Variant summary

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

The NM_080860.4(RSPH1):c.919C>T(p.Leu307Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,610,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.295

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]

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=0.005535573).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH1	NM_080860.4	c.919C>T	p.Leu307Phe	missense_variant	9/9	ENST00000291536.8
RSPH1	NM_001286506.2	c.805C>T	p.Leu269Phe	missense_variant	8/8
RSPH1	XM_011529786.2	c.847C>T	p.Leu283Phe	missense_variant	8/8
RSPH1	XM_005261208.3	c.712C>T	p.Leu238Phe	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH1	ENST00000291536.8	c.919C>T	p.Leu307Phe	missense_variant	9/9	1	NM_080860.4	P1
RSPH1	ENST00000398352.3	c.805C>T	p.Leu269Phe	missense_variant	8/8	5
RSPH1	ENST00000493019.1	n.2537C>T		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 250970 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135620

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000985

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000802 AC: 117 AN: 1458038 Hom.: 0 Cov.: 27 AF XY: 0.0000951 AC XY: 69 AN XY: 725634

Gnomad4 AFR exome AF: 0.00204

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74456

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000835 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000222 AC: 27

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

Invitae

Sep 07, 2022

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 307 of the RSPH1 protein (p.Leu307Phe). This variant is present in population databases (rs141886699, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with RSPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 454953). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	11
Dann	Benign	0.96
DEOGEN2	Benign	0.041	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.81	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.064	T;T
Polyphen		0.21	B;.
Vest4		0.14
MVP		0.040
MPC		0.29
ClinPred		0.0022	T
GERP RS		-2.9
Varity_R		0.12
gMVP		0.024

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: rs141886699; hg19: chr21-43892939;