rs201034280

Positions:

• chr21-42485662-G-A

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.501+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,966 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (13 hom.)
• Consequence: RSPH1 NM_080860.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004772
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.689

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=-0.57).
• BP6: Variant 21-42485662-G-A is Benign according to our data. Variant chr21-42485662-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241785.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 = 0.00175 (267/152152) while in subpopulation NFE AF= 0.00338 (230/68026). AF 95% confidence interval is 0.00302. There are 0 homozygotes in gnomad4. There are 118 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.501+7C>T		splice_region_variant, intron_variant		ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.387+7C>T		splice_region_variant, intron_variant			NP_001273435.1
RSPH1	XM_011529786.2	c.501+7C>T		splice_region_variant, intron_variant			XP_011528088.1
RSPH1	XM_005261208.3	c.294+7C>T		splice_region_variant, intron_variant			XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.501+7C>T		splice_region_variant, intron_variant		1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3	c.387+7C>T		splice_region_variant, intron_variant		5		ENSP00000381395.3
RSPH1	ENST00000493019.1	n.1134C>T		non_coding_transcript_exon_variant	4/8	2

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 267 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00200 AC: 504 AN: 251390 Hom.: 3 AF XY: 0.00208 AC XY: 282 AN XY: 135856

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00405

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00292 AC: 4267 AN: 1461814 Hom.: 13 Cov.: 30 AF XY: 0.00277 AC XY: 2018 AN XY: 727222

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00363

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.00159 AC XY: 118 AN XY: 74322

Gnomad4 AFR AF: 0.000507

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00265 Hom.: 1

Bravo AF: 0.00161

EpiCase AF: 0.00322

EpiControl AF: 0.00255

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

RSPH1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.1
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.020		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: rs201034280; hg19: chr21-43905772;