rs2839536

Positions:

• chr21-42485777-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_080860.4(RSPH1):​c.393G>A​(p.Ala131=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,626 control chromosomes in the GnomAD database, including 125,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9560 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115763 hom.)
• Consequence: RSPH1 NM_080860.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.39

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 21-42485777-C-T is Benign according to our data. Variant chr21-42485777-C-T is described in ClinVar as [Benign]. Clinvar id is 227050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.393G>A	p.Ala131=	synonymous_variant	5/9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.279G>A	p.Ala93=	synonymous_variant	4/8		NP_001273435.1
RSPH1	XM_011529786.2	c.393G>A	p.Ala131=	synonymous_variant	5/8		XP_011528088.1
RSPH1	XM_005261208.3	c.186G>A	p.Ala62=	synonymous_variant	3/7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.393G>A	p.Ala131=	synonymous_variant	5/9	1	NM_080860.4	ENSP00000291536	P1
RSPH1	ENST00000398352.3	c.279G>A	p.Ala93=	synonymous_variant	4/8	5		ENSP00000381395
RSPH1	ENST00000493019.1	n.1019G>A		non_coding_transcript_exon_variant	4/8	2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49473 AN: 151918 Hom.: 9559 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.346

GnomAD3 exomes AF: 0.382 AC: 96012 AN: 251430 Hom.: 21163 AF XY: 0.373 AC XY: 50723 AN XY: 135892

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.673

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.292

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.389 AC: 568517 AN: 1461588 Hom.: 115763 Cov.: 42 AF XY: 0.385 AC XY: 279789 AN XY: 727122

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.653

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.295

Gnomad4 FIN exome AF: 0.385

Gnomad4 NFE exome AF: 0.404

Gnomad4 OTH exome AF: 0.368

GnomAD4 genome AF: 0.326 AC: 49492 AN: 152038 Hom.: 9560 Cov.: 33 AF XY: 0.328 AC XY: 24348 AN XY: 74288

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.533

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.297

Gnomad4 FIN AF: 0.386

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.342

Alfa AF: 0.380 Hom.: 23599

Bravo AF: 0.330

Asia WGS AF: 0.234 AC: 818 AN: 3478

EpiCase AF: 0.388

EpiControl AF: 0.384

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Ala131Ala in exon 5 of RSPH1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 39.3% (3379/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2839536). -

Primary ciliary dyskinesia 24 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.29
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs2839536; hg19: chr21-43905887; COSMIC: COSV52318402;