21-42477439-T-C

Position:

• chr21-42477439-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000291536.8(RSPH1):​c.579A>G​(p.Arg193=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,613,592 control chromosomes in the GnomAD database, including 1,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (92 hom., cov: 34)
  • Exomes 𝑓: 0.037 (1159 hom.)
• Consequence: RSPH1 ENST00000291536.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.08

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=-0.59).
• BP6: Variant 21-42477439-T-C is Benign according to our data. Variant chr21-42477439-T-C is described in ClinVar as [Benign]. Clinvar id is 227051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0296 (4515/152390) while in subpopulation NFE AF= 0.0415 (2822/68030). AF 95% confidence interval is 0.0402. There are 92 homozygotes in gnomad4. There are 2265 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 92 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.579A>G	p.Arg193=	synonymous_variant	7/9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.465A>G	p.Arg155=	synonymous_variant	6/8		NP_001273435.1
RSPH1	XM_011529786.2	c.507A>G	p.Arg169=	synonymous_variant	6/8		XP_011528088.1
RSPH1	XM_005261208.3	c.372A>G	p.Arg124=	synonymous_variant	5/7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.579A>G	p.Arg193=	synonymous_variant	7/9	1	NM_080860.4	ENSP00000291536	P1
RSPH1	ENST00000398352.3	c.465A>G	p.Arg155=	synonymous_variant	6/8	5		ENSP00000381395
RSPH1	ENST00000493019.1	n.2197A>G		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4520 AN: 152272 Hom.: 92 Cov.: 34

Gnomad AFR AF: 0.00694

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.0533

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0339

GnomAD3 exomes AF: 0.0336 AC: 8435 AN: 251312 Hom.: 210 AF XY: 0.0356 AC XY: 4835 AN XY: 135862

Gnomad AFR exome AF: 0.00622

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0613

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0419

Gnomad FIN exome AF: 0.0501

Gnomad NFE exome AF: 0.0397

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0369 AC: 53934 AN: 1461202 Hom.: 1159 Cov.: 33 AF XY: 0.0375 AC XY: 27274 AN XY: 726916

Gnomad4 AFR exome AF: 0.00535

Gnomad4 AMR exome AF: 0.0187

Gnomad4 ASJ exome AF: 0.0615

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0411

Gnomad4 FIN exome AF: 0.0483

Gnomad4 NFE exome AF: 0.0385

Gnomad4 OTH exome AF: 0.0366

GnomAD4 genome AF: 0.0296 AC: 4515 AN: 152390 Hom.: 92 Cov.: 34 AF XY: 0.0304 AC XY: 2265 AN XY: 74524

Gnomad4 AFR AF: 0.00690

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.0608

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0327

Gnomad4 FIN AF: 0.0533

Gnomad4 NFE AF: 0.0415

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0378 Hom.: 58

Bravo AF: 0.0261

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0405

EpiControl AF: 0.0418

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2019	- -
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

Arg193Arg in exon 7 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 4.4% (376/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs149478284). -

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	-0.59
CADD	Benign	7.0
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs149478284; hg19: chr21-43897549; COSMIC: COSV52319309;