6-116632266-C-G

Variant names:

• chr6-116632266-C-G
• rs372634959
• NM_001010892.3:c.1976C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001010892.3(RSPH4A):​c.1976C>G​(p.Pro659Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P659L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.44
• Publications: 0 publications found

Genes affected

RSPH4A (HGNC:21558): (radial spoke head component 4A) This gene encodes a protein that appears to be a component the radial spoke head, as determined by homology to similar proteins in the biflagellate alga Chlamydomonas reinhardtii and other ciliates. Radial spokes, which are regularly spaced along cilia, sperm, and flagella axonemes, consist of a thin 'stalk' and a bulbous 'head' that form a signal transduction scaffold between the central pair of microtubules and dynein. Mutations in this gene cause primary ciliary dyskinesia 1, a disease arising from dysmotility of motile cilia and sperm. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

RSPH4A Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 11

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124901386 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010892.3. 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
	RSPH4A	NM_001010892.3	MANE Select	c.1976C>G	p.Pro659Arg	missense	Exon 6 of 6	NP_001010892.1	Q5TD94-1
	RSPH4A	NM_001161664.2		c.*37C>G		3_prime_UTR	Exon 5 of 5	NP_001155136.1	Q5TD94-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH4A	ENST00000229554.10	TSL:1 MANE Select	c.1976C>G	p.Pro659Arg	missense	Exon 6 of 6	ENSP00000229554.5	Q5TD94-1
	RSPH4A	ENST00000368581.8	TSL:1	c.*37C>G		3_prime_UTR	Exon 5 of 5	ENSP00000357570.4	Q5TD94-3
	RSPH4A	ENST00000368580.4	TSL:5	c.1235C>G	p.Pro412Arg	missense	Exon 5 of 5	ENSP00000357569.4	Q5TD94-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460312 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726514

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4714

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111754

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.68		Loss of glycosylation at P659 (P = 0.0262)
MVP		0.74
MPC		0.64
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.85
gMVP		0.85
Mutation Taster		=34/66	disease causing

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: rs372634959; hg19: chr6-116953429;