21-42477439-T-C

Variant names:

• chr21-42477439-T-C
• rs149478284
• NM_080860.4:c.579A>G

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.579A>G​(p.Arg193Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,613,592 control chromosomes in the GnomAD database, including 1,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (92 hom., cov: 34)
  • Exomes 𝑓: 0.037 (1159 hom.)
• Consequence: RSPH1 NM_080860.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.08
• Publications: 5 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• 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=-0.59).
• BP6: Variant 21-42477439-T-C is Benign according to our data. Variant chr21-42477439-T-C is described in ClinVar as Benign. ClinVar VariationId is 227051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0296 (4515/152390) while in subpopulation NFE AF = 0.0415 (2822/68030). AF 95% confidence interval is 0.0402. There are 92 homozygotes in GnomAd4. There are 2265 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 92 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	NM_080860.4	MANE Select	c.579A>G	p.Arg193Arg	synonymous	Exon 7 of 9	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.465A>G	p.Arg155Arg	synonymous	Exon 6 of 8	NP_001273435.1	Q8WYR4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH1	ENST00000291536.8	TSL:1 MANE Select	c.579A>G	p.Arg193Arg	synonymous	Exon 7 of 9	ENSP00000291536.3	Q8WYR4-1
	RSPH1	ENST00000856519.1		c.507A>G	p.Arg169Arg	synonymous	Exon 6 of 8	ENSP00000526578.1
	RSPH1	ENST00000398352.3	TSL:5	c.465A>G	p.Arg155Arg	synonymous	Exon 6 of 8	ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes AF: 0.0297 AC: 4520 AN: 152272 Hom.: 92 Cov.: 34

Gnomad AFR AF: 0.00694

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0608

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0329

Gnomad FIN AF: 0.0533

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0415

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0336 AC: 8435 AN: 251312 AF XY: 0.0356

Gnomad AFR exome AF: 0.00622

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0613

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0501

Gnomad NFE exome AF: 0.0397

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0369 AC: 53934 AN: 1461202 Hom.: 1159 Cov.: 33 AF XY: 0.0375 AC XY: 27274 AN XY: 726916

African (AFR) AF: 0.00535 AC: 179 AN: 33474

American (AMR) AF: 0.0187 AC: 836 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0615 AC: 1608 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0411 AC: 3540 AN: 86232

European-Finnish (FIN) AF: 0.0483 AC: 2579 AN: 53352

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5766

European-Non Finnish (NFE) AF: 0.0385 AC: 42751 AN: 1111446

Other (OTH) AF: 0.0366 AC: 2212 AN: 60382

GnomAD4 genome AF: 0.0296 AC: 4515 AN: 152390 Hom.: 92 Cov.: 34 AF XY: 0.0304 AC XY: 2265 AN XY: 74524

African (AFR) AF: 0.00690 AC: 287 AN: 41606

American (AMR) AF: 0.0223 AC: 342 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 211 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5194

South Asian (SAS) AF: 0.0327 AC: 158 AN: 4832

European-Finnish (FIN) AF: 0.0533 AC: 566 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0415 AC: 2822 AN: 68030

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0378 Hom.: 58

Bravo AF: 0.0261

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0405

EpiControl AF: 0.0418

ClinVar

ClinVar submissions

Significance: 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	-0.59
CADD	Benign	7.0
DANN	Benign	0.73
PhyloP100		2.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs149478284; hg19: chr21-43897549; COSMIC: COSV52319309;