rs562591045

Variant names:

• chr21-42477345-G-A
• rs562591045
• NM_080860.4:c.673C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_080860.4(RSPH1):​c.673C>T​(p.Pro225Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,610,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P225L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.202
• 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01617968).

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.673C>T	p.Pro225Ser	missense	Exon 7 of 9	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.559C>T	p.Pro187Ser	missense	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.673C>T	p.Pro225Ser	missense	Exon 7 of 9	ENSP00000291536.3	Q8WYR4-1
	RSPH1	ENST00000856519.1		c.601C>T	p.Pro201Ser	missense	Exon 6 of 8	ENSP00000526578.1
	RSPH1	ENST00000398352.3	TSL:5	c.559C>T	p.Pro187Ser	missense	Exon 6 of 8	ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 35 AN: 148272 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

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: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251326 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461736 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 727158

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000403 AC: 18 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111940

Other (OTH) AF: 0.000182 AC: 11 AN: 60386

GnomAD4 genome AF: 0.000236 AC: 35 AN: 148390 Hom.: 0 Cov.: 34 AF XY: 0.000207 AC XY: 15 AN XY: 72358

African (AFR) AF: 0.00 AC: 0 AN: 40398

American (AMR) AF: 0.00236 AC: 35 AN: 14820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.00 AC: 0 AN: 4666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66568

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000431

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.65
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.20
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.059
Sift	Benign	0.48	T
Sift4G	Benign	0.83	T
Polyphen		0.010	B
Vest4		0.19
MutPred		0.20		Gain of sheet (P = 0.039)
MVP		0.14
MPC		0.11
ClinPred		0.019	T
GERP RS		0.86
Varity_R		0.026
gMVP		0.28
Mutation Taster		=96/4	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: rs562591045; hg19: chr21-43897455;