rs75626002

chr21-42477307-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_080860.4(RSPH1):c.711C>T(p.Asp237=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,586,702 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: RSPH1 NM_080860.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.23

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-42477307-G-A is Benign according to our data. Variant chr21-42477307-G-A is described in ClinVar as [Benign]. Clinvar id is 454949.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00116 (167/144206) while in subpopulation AFR AF= 0.00384 (152/39596). AF 95% confidence interval is 0.00334. There are 2 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH1	NM_080860.4	c.711C>T	p.Asp237=	synonymous_variant	7/9	ENST00000291536.8
RSPH1	NM_001286506.2	c.597C>T	p.Asp199=	synonymous_variant	6/8
RSPH1	XM_011529786.2	c.639C>T	p.Asp213=	synonymous_variant	6/8
RSPH1	XM_005261208.3	c.504C>T	p.Asp168=	synonymous_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH1	ENST00000291536.8	c.711C>T	p.Asp237=	synonymous_variant	7/9	1	NM_080860.4	P1
RSPH1	ENST00000398352.3	c.597C>T	p.Asp199=	synonymous_variant	6/8	5
RSPH1	ENST00000493019.1	n.2329C>T		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 167 AN: 144088 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000761

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.000709 AC: 178 AN: 250968 Hom.: 1 AF XY: 0.000442 AC XY: 60 AN XY: 135742

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000174 AC: 251 AN: 1442496 Hom.: 1 Cov.: 34 AF XY: 0.000149 AC XY: 107 AN XY: 717654

Gnomad4 AFR exome AF: 0.00610

Gnomad4 AMR exome AF: 0.000248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000196

Gnomad4 NFE exome AF: 0.0000100

Gnomad4 OTH exome AF: 0.000405

GnomAD4 genome AF: 0.00116 AC: 167 AN: 144206 Hom.: 2 Cov.: 33 AF XY: 0.00105 AC XY: 74 AN XY: 70192

Gnomad4 AFR AF: 0.00384

Gnomad4 AMR AF: 0.000760

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00197

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00325

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	3.0
Dann	Benign	0.74

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: rs75626002; hg19: chr21-43897417; COSMIC: COSV52320598;