rs556286752

Variant names:

• chr21-42477337-CT-C
• NM_080860.4:c.680delA

Your query was ambiguous. Multiple possible variants found:

• chr21-42477337-CT-C
• chr21-42477337-CT-CTT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_080860.4(RSPH1):​c.680delA​(p.Lys227SerfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RSPH1 NM_080860.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH1	NM_080860.4	c.680delA	p.Lys227SerfsTer38	frameshift_variant	Exon 7 of 9	ENST00000291536.8	NP_543136.1
RSPH1	NM_001286506.2	c.566delA	p.Lys189SerfsTer38	frameshift_variant	Exon 6 of 8		NP_001273435.1
RSPH1	XM_011529786.2	c.608delA	p.Lys203SerfsTer38	frameshift_variant	Exon 6 of 8		XP_011528088.1
RSPH1	XM_005261208.3	c.473delA	p.Lys158SerfsTer38	frameshift_variant	Exon 5 of 7		XP_005261265.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH1	ENST00000291536.8	c.680delA	p.Lys227SerfsTer38	frameshift_variant	Exon 7 of 9	1	NM_080860.4	ENSP00000291536.3
RSPH1	ENST00000398352.3	c.566delA	p.Lys189SerfsTer38	frameshift_variant	Exon 6 of 8	5		ENSP00000381395.3
RSPH1	ENST00000493019.1	n.2298delA		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461602 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-43897447;