rs75626002

Variant names:

• chr21-42477307-G-A
• rs75626002
• NM_080860.4:c.711C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_080860.4(RSPH1):​c.711C>T​(p.Asp237Asp) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.23
• 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 -21 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 VariationId is 454949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080860.4. 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.711C>T	p.Asp237Asp	synonymous	Exon 7 of 9	NP_543136.1
	RSPH1	NM_001286506.2		c.597C>T	p.Asp199Asp	synonymous	Exon 6 of 8	NP_001273435.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	ENST00000291536.8	TSL:1 MANE Select	c.711C>T	p.Asp237Asp	synonymous	Exon 7 of 9	ENSP00000291536.3
	RSPH1	ENST00000398352.3	TSL:5	c.597C>T	p.Asp199Asp	synonymous	Exon 6 of 8	ENSP00000381395.3
	RSPH1	ENST00000493019.1	TSL:2	n.2329C>T		non_coding_transcript_exon	Exon 6 of 8

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

GnomAD2 exomes AF: 0.000709 AC: 178 AN: 250968 AF XY: 0.000442

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 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

African (AFR) AF: 0.00610 AC: 201 AN: 32926

American (AMR) AF: 0.000248 AC: 11 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25814

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38342

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85976

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 50908

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5724

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1099056

Other (OTH) AF: 0.000405 AC: 24 AN: 59328

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

African (AFR) AF: 0.00384 AC: 152 AN: 39596

American (AMR) AF: 0.000760 AC: 11 AN: 14470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 4828

South Asian (SAS) AF: 0.00 AC: 0 AN: 4544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9294

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64846

Other (OTH) AF: 0.00197 AC: 4 AN: 2030

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00325

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.0
DANN	Benign	0.74
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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