rs143552625

Variant names:

• chr21-42475916-G-A
• rs143552625
• NM_080860.4:c.859C>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.859C>T​(p.Arg287Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000708 in 1,611,144 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. R287H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: RSPH1 NM_080860.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.832
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055344105).

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.859C>T	p.Arg287Cys	missense	Exon 8 of 9	NP_543136.1	Q8WYR4-1
	RSPH1	NM_001286506.2		c.745C>T	p.Arg249Cys	missense	Exon 7 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.859C>T	p.Arg287Cys	missense	Exon 8 of 9	ENSP00000291536.3	Q8WYR4-1
	RSPH1	ENST00000856519.1		c.787C>T	p.Arg263Cys	missense	Exon 7 of 8	ENSP00000526578.1
	RSPH1	ENST00000398352.3	TSL:5	c.745C>T	p.Arg249Cys	missense	Exon 7 of 8	ENSP00000381395.3	Q8WYR4-2

Frequencies

GnomAD3 genomes AF: 0.000509 AC: 76 AN: 149186 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000402

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000963

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000963

Gnomad OTH AF: 0.000496

GnomAD2 exomes AF: 0.000445 AC: 112 AN: 251424 AF XY: 0.000390

Gnomad AFR exome AF: 0.000185

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: 0.000862

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000729 AC: 1065 AN: 1461842 Hom.: 1 Cov.: 31 AF XY: 0.000712 AC XY: 518 AN XY: 727230

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.000922 AC: 1025 AN: 1111984

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.000509 AC: 76 AN: 149302 Hom.: 0 Cov.: 28 AF XY: 0.000468 AC XY: 34 AN XY: 72622

African (AFR) AF: 0.0000986 AC: 4 AN: 40576

American (AMR) AF: 0.000202 AC: 3 AN: 14844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.000403 AC: 2 AN: 4966

South Asian (SAS) AF: 0.00 AC: 0 AN: 4350

European-Finnish (FIN) AF: 0.0000963 AC: 1 AN: 10382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000963 AC: 65 AN: 67492

Other (OTH) AF: 0.000491 AC: 1 AN: 2038

Alfa AF: 0.000718 Hom.: 0

Bravo AF: 0.000510

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.83
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.097
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.022	D
Polyphen		0.95	P
Vest4		0.40
MVP		0.30
MPC		0.42
ClinPred		0.039	T
GERP RS		1.4
Varity_R		0.13
gMVP		0.095
Mutation Taster		=94/6	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: rs143552625; hg19: chr21-43896026;