NM_080860.4:c.393G>A

Variant names:

• chr21-42485777-C-T
• rs2839536
• NM_080860.4:c.393G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_080860.4(RSPH1):​c.393G>A​(p.Ala131Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,626 control chromosomes in the GnomAD database, including 125,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9560 hom., cov: 33)
  • Exomes 𝑓: 0.39 (115763 hom.)
• Consequence: RSPH1 NM_080860.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.39
• Publications: 22 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=-0.53).
• BP6: Variant 21-42485777-C-T is Benign according to our data. Variant chr21-42485777-C-T is described in ClinVar as Benign. ClinVar VariationId is 227050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

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.393G>A	p.Ala131Ala	synonymous	Exon 5 of 9	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.279G>A	p.Ala93Ala	synonymous	Exon 4 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.393G>A	p.Ala131Ala	synonymous	Exon 5 of 9	ENSP00000291536.3	Q8WYR4-1
	RSPH1	ENST00000856519.1		c.393G>A	p.Ala131Ala	synonymous	Exon 5 of 8	ENSP00000526578.1
	RSPH1	ENST00000398352.3	TSL:5	c.279G>A	p.Ala93Ala	synonymous	Exon 4 of 8	ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49473 AN: 151918 Hom.: 9559 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.346

GnomAD2 exomes AF: 0.382 AC: 96012 AN: 251430 AF XY: 0.373

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.673

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.193

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.389 AC: 568517 AN: 1461588 Hom.: 115763 Cov.: 42 AF XY: 0.385 AC XY: 279789 AN XY: 727122

African (AFR) AF: 0.120 AC: 4002 AN: 33472

American (AMR) AF: 0.653 AC: 29183 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 9005 AN: 26134

East Asian (EAS) AF: 0.183 AC: 7250 AN: 39696

South Asian (SAS) AF: 0.295 AC: 25418 AN: 86254

European-Finnish (FIN) AF: 0.385 AC: 20560 AN: 53388

Middle Eastern (MID) AF: 0.254 AC: 1467 AN: 5766

European-Non Finnish (NFE) AF: 0.404 AC: 449391 AN: 1111772

Other (OTH) AF: 0.368 AC: 22241 AN: 60384

GnomAD4 genome AF: 0.326 AC: 49492 AN: 152038 Hom.: 9560 Cov.: 33 AF XY: 0.328 AC XY: 24348 AN XY: 74288

African (AFR) AF: 0.132 AC: 5460 AN: 41498

American (AMR) AF: 0.533 AC: 8144 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1244 AN: 3472

East Asian (EAS) AF: 0.192 AC: 992 AN: 5174

South Asian (SAS) AF: 0.297 AC: 1433 AN: 4820

European-Finnish (FIN) AF: 0.386 AC: 4066 AN: 10530

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26927 AN: 67960

Other (OTH) AF: 0.342 AC: 720 AN: 2106

Alfa AF: 0.372 Hom.: 44094

Bravo AF: 0.330

Asia WGS AF: 0.234 AC: 818 AN: 3478

EpiCase AF: 0.388

EpiControl AF: 0.384

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)
-	-	1	Primary ciliary dyskinesia 24 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.29
DANN	Benign	0.86
PhyloP100		-2.4
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs2839536; hg19: chr21-43905887; COSMIC: COSV52318402;