rs116480603

Positions:

• chr21-42493014-G-A

Variant summary

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

The NM_080860.4(RSPH1):​c.120C>T​(p.Asn40=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,614,142 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (30 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (29 hom.)
• Consequence: RSPH1 NM_080860.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.23

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 21-42493014-G-A is Benign according to our data. Variant chr21-42493014-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 241781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00937 (1427/152258) while in subpopulation AFR AF= 0.0324 (1346/41524). AF 95% confidence interval is 0.031. There are 30 homozygotes in gnomad4. There are 690 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH1	NM_080860.4	c.120C>T	p.Asn40=	synonymous_variant	2/9	ENST00000291536.8
RSPH1	XM_011529786.2	c.120C>T	p.Asn40=	synonymous_variant	2/8
RSPH1	NM_001286506.2	c.55-151C>T		intron_variant
RSPH1	XM_005261208.3	c.67+3106C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH1	ENST00000291536.8	c.120C>T	p.Asn40=	synonymous_variant	2/9	1	NM_080860.4	P1
RSPH1	ENST00000398352.3	c.55-151C>T		intron_variant		5
RSPH1	ENST00000493019.1	n.180C>T		non_coding_transcript_exon_variant	2/8	2

Frequencies

GnomAD3 genomes AF: 0.00937 AC: 1425 AN: 152142 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00231 AC: 581 AN: 251480 Hom.: 13 AF XY: 0.00174 AC XY: 237 AN XY: 135916

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000984 AC: 1438 AN: 1461884 Hom.: 29 Cov.: 31 AF XY: 0.000846 AC XY: 615 AN XY: 727244

Gnomad4 AFR exome AF: 0.0352

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00937 AC: 1427 AN: 152258 Hom.: 30 Cov.: 33 AF XY: 0.00927 AC XY: 690 AN XY: 74456

Gnomad4 AFR AF: 0.0324

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00541 Hom.: 2

Bravo AF: 0.0111

Asia WGS AF: 0.00202 AC: 7 AN: 3478

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

Invitae

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2022

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.66
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs116480603; hg19: chr21-43913124;