21-42477439-T-C

Variant names:

• chr21-42477439-T-C
• rs149478284
• NM_080860.4:c.579A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_080860.4(RSPH1):​c.579A>G​(p.Arg193Arg) 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 NM_080860.4 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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 92 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.579A>G	p.Arg193Arg	synonymous_variant	Exon 7 of 9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.465A>G	p.Arg155Arg	synonymous_variant	Exon 6 of 8		NP_001273435.1
RSPH1	XM_011529786.2	c.507A>G	p.Arg169Arg	synonymous_variant	Exon 6 of 8		XP_011528088.1
RSPH1	XM_005261208.3	c.372A>G	p.Arg124Arg	synonymous_variant	Exon 5 of 7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.579A>G	p.Arg193Arg	synonymous_variant	Exon 7 of 9	1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3	c.465A>G	p.Arg155Arg	synonymous_variant	Exon 6 of 8	5		ENSP00000381395.3
RSPH1	ENST00000493019.1	n.2197A>G		non_coding_transcript_exon_variant	Exon 6 of 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

GnomAD2 exomes AF: 0.0336 AC: 8435 AN: 251312 AF XY: 0.0356

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 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 AC: 179 AN: 33474

Gnomad4 AMR exome AF: 0.0187 AC: 836 AN: 44722

Gnomad4 ASJ exome AF: 0.0615 AC: 1608 AN: 26128

Gnomad4 EAS exome AF: 0.0000756 AC: 3 AN: 39700

Gnomad4 SAS exome AF: 0.0411 AC: 3540 AN: 86232

Gnomad4 FIN exome AF: 0.0483 AC: 2579 AN: 53352

Gnomad4 NFE exome AF: 0.0385 AC: 42751 AN: 1111446

Gnomad4 Remaining exome AF: 0.0366 AC: 2212 AN: 60382

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 AC: 0.00689804 AN: 0.00689804

Gnomad4 AMR AF: 0.0223 AC: 0.0223325 AN: 0.0223325

Gnomad4 ASJ AF: 0.0608 AC: 0.0607719 AN: 0.0607719

Gnomad4 EAS AF: 0.000578 AC: 0.00057759 AN: 0.00057759

Gnomad4 SAS AF: 0.0327 AC: 0.0326987 AN: 0.0326987

Gnomad4 FIN AF: 0.0533 AC: 0.0532957 AN: 0.0532957

Gnomad4 NFE AF: 0.0415 AC: 0.0414817 AN: 0.0414817

Gnomad4 OTH AF: 0.0336 AC: 0.0335539 AN: 0.0335539

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

Jun 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.0
DANN	Benign	0.73
Mutation Taster		=98/2	polymorphism (auto)

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;