rs150629342

chr21-42472841-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_080860.4(RSPH1):c.907A>G(p.Arg303Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,609,748 control chromosomes in the GnomAD database, including 7 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (7 hom.)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.46

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006163895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH1	NM_080860.4	c.907A>G	p.Arg303Gly	missense_variant	9/9	ENST00000291536.8
RSPH1	NM_001286506.2	c.793A>G	p.Arg265Gly	missense_variant	8/8
RSPH1	XM_011529786.2	c.835A>G	p.Arg279Gly	missense_variant	8/8
RSPH1	XM_005261208.3	c.700A>G	p.Arg234Gly	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH1	ENST00000291536.8	c.907A>G	p.Arg303Gly	missense_variant	9/9	1	NM_080860.4	P1
RSPH1	ENST00000398352.3	c.793A>G	p.Arg265Gly	missense_variant	8/8	5
RSPH1	ENST00000493019.1	n.2525A>G		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000872 AC: 219 AN: 251104 Hom.: 1 AF XY: 0.000943 AC XY: 128 AN XY: 135698

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00207

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00118 AC: 1719 AN: 1457382 Hom.: 7 Cov.: 27 AF XY: 0.00119 AC XY: 866 AN XY: 725382

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00218

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00131

Gnomad4 OTH exome AF: 0.000764

GnomAD4 genome AF: 0.000774 AC: 118 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000872 AC XY: 65 AN XY: 74512

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000506

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 17, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.907A>G (p.R303G) alteration is located in exon 9 (coding exon 9) of the RSPH1 gene. This alteration results from a A to G substitution at nucleotide position 907, causing the arginine (R) at amino acid position 303 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia 24 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 11, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	16
Dann	Benign	0.93
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.76	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.90	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.039	D;D
Polyphen		0.61	P;.
Vest4		0.20
MVP		0.31
MPC		0.17
ClinPred		0.033	T
GERP RS		3.0
Varity_R		0.14
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150629342; hg19: chr21-43892951;