21-42486358-A-G

Position:

• chr21-42486358-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080860.4(RSPH1):​c.365+13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00459 in 1,589,096 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (37 hom.)
• Consequence: RSPH1 NM_080860.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.776

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]

RSPH1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 21-42486358-A-G is Benign according to our data. Variant chr21-42486358-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 504821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00462 (704/152304) while in subpopulation NFE AF= 0.00697 (474/68026). AF 95% confidence interval is 0.00645. There are 3 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.365+13T>C		intron_variant		ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.251+13T>C		intron_variant			NP_001273435.1
RSPH1	XM_011529786.2	c.365+13T>C		intron_variant			XP_011528088.1
RSPH1	XM_005261208.3	c.158+13T>C		intron_variant			XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.365+13T>C		intron_variant		1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3	c.251+13T>C		intron_variant		5		ENSP00000381395.3
RSPH1	ENST00000493019.1	n.438T>C		non_coding_transcript_exon_variant	4/8	2

Frequencies

GnomAD3 genomes AF: 0.00463 AC: 704 AN: 152186 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00697

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00438 AC: 1100 AN: 251404 Hom.: 6 AF XY: 0.00452 AC XY: 614 AN XY: 135854

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.00562

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00459 AC: 6590 AN: 1436792 Hom.: 37 Cov.: 27 AF XY: 0.00472 AC XY: 3385 AN XY: 716440

Gnomad4 AFR exome AF: 0.000577

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00338

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.0132

Gnomad4 NFE exome AF: 0.00489

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00462 AC: 704 AN: 152304 Hom.: 3 Cov.: 33 AF XY: 0.00478 AC XY: 356 AN XY: 74478

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.00697

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00714 Hom.: 2

Bravo AF: 0.00315

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2020	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

365+13T>C in intron 4 of RSPH1: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 0.6% (55/8600) of European American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS; dbSNP rs181902996). -

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	-0.88
CADD	Benign	0.21
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs181902996; hg19: chr21-43906468;