rs181902996

Variant names:

• chr21-42486358-A-G
• rs181902996
• NM_080860.4:c.365+13T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000291536.8(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 ENST00000291536.8 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.776
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 24

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000291536.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	NM_080860.4	MANE Select	c.365+13T>C		intron	N/A	NP_543136.1
	RSPH1	NM_001286506.2		c.251+13T>C		intron	N/A	NP_001273435.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	ENST00000291536.8	TSL:1 MANE Select	c.365+13T>C		intron	N/A	ENSP00000291536.3
	RSPH1	ENST00000493019.1	TSL:2	n.438T>C		non_coding_transcript_exon	Exon 4 of 8
	RSPH1	ENST00000398352.3	TSL:5	c.251+13T>C		intron	N/A	ENSP00000381395.3

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

GnomAD2 exomes AF: 0.00438 AC: 1100 AN: 251404 AF XY: 0.00452

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 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

African (AFR) AF: 0.000577 AC: 19 AN: 32928

American (AMR) AF: 0.00163 AC: 73 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00338 AC: 88 AN: 26006

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39550

South Asian (SAS) AF: 0.00141 AC: 121 AN: 85762

European-Finnish (FIN) AF: 0.0132 AC: 704 AN: 53400

Middle Eastern (MID) AF: 0.00227 AC: 13 AN: 5728

European-Non Finnish (NFE) AF: 0.00489 AC: 5323 AN: 1089176

Other (OTH) AF: 0.00416 AC: 248 AN: 59564

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

African (AFR) AF: 0.000506 AC: 21 AN: 41536

American (AMR) AF: 0.00216 AC: 33 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00697 AC: 474 AN: 68026

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00714 Hom.: 2

Bravo AF: 0.00315

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.21
DANN	Benign	0.34
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs181902996; hg19: chr21-43906468;