NM_001010892.3:c.1766T>C

Variant names:

• chr6-116629670-T-C
• rs784133
• NM_001010892.3:c.1766T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001010892.3(RSPH4A):​c.1766T>C​(p.Leu589Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,608,076 control chromosomes in the GnomAD database, including 314,154 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (38064 hom., cov: 32)
  • Exomes 𝑓: 0.61 (276090 hom.)
• Consequence: RSPH4A NM_001010892.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.41
• Publications: 33 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: PanelApp Australia, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC124901386 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.54601E-7).
• BP6: Variant 6-116629670-T-C is Benign according to our data. Variant chr6-116629670-T-C is described in ClinVar as Benign. ClinVar VariationId is 165061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

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.1766T>C	p.Leu589Pro	missense	Exon 4 of 6	NP_001010892.1	Q5TD94-1
	RSPH4A	NM_001161664.2		c.1663-765T>C		intron	N/A	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.1766T>C	p.Leu589Pro	missense	Exon 4 of 6	ENSP00000229554.5	Q5TD94-1
	RSPH4A	ENST00000368581.8	TSL:1	c.1663-765T>C		intron	N/A	ENSP00000357570.4	Q5TD94-3
	RSPH4A	ENST00000368580.4	TSL:5	c.1025T>C	p.Leu342Pro	missense	Exon 3 of 5	ENSP00000357569.4	Q5TD94-2

Frequencies

GnomAD3 genomes AF: 0.691 AC: 105052 AN: 151974 Hom.: 37993 Cov.: 32

Gnomad AFR AF: 0.921

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.636

Gnomad ASJ AF: 0.570

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.638 AC: 158674 AN: 248794 AF XY: 0.635

Gnomad AFR exome AF: 0.927

Gnomad AMR exome AF: 0.657

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.504

Gnomad FIN exome AF: 0.616

Gnomad NFE exome AF: 0.594

Gnomad OTH exome AF: 0.617

GnomAD4 exome AF: 0.612 AC: 890812 AN: 1455984 Hom.: 276090 Cov.: 36 AF XY: 0.614 AC XY: 444669 AN XY: 724616

African (AFR) AF: 0.930 AC: 31067 AN: 33406

American (AMR) AF: 0.660 AC: 29534 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 14812 AN: 26102

East Asian (EAS) AF: 0.537 AC: 21309 AN: 39654

South Asian (SAS) AF: 0.741 AC: 63843 AN: 86156

European-Finnish (FIN) AF: 0.619 AC: 33013 AN: 53364

Middle Eastern (MID) AF: 0.589 AC: 3371 AN: 5726

European-Non Finnish (NFE) AF: 0.593 AC: 656598 AN: 1106662

Other (OTH) AF: 0.619 AC: 37265 AN: 60196

GnomAD4 genome AF: 0.692 AC: 105191 AN: 152092 Hom.: 38064 Cov.: 32 AF XY: 0.690 AC XY: 51310 AN XY: 74338

African (AFR) AF: 0.921 AC: 38236 AN: 41510

American (AMR) AF: 0.636 AC: 9715 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 1977 AN: 3468

East Asian (EAS) AF: 0.508 AC: 2629 AN: 5178

South Asian (SAS) AF: 0.738 AC: 3559 AN: 4822

European-Finnish (FIN) AF: 0.621 AC: 6558 AN: 10562

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40507 AN: 67974

Other (OTH) AF: 0.651 AC: 1369 AN: 2102

Alfa AF: 0.636 Hom.: 61715

Bravo AF: 0.697

TwinsUK AF: 0.609 AC: 2259

ALSPAC AF: 0.601 AC: 2317

ESP6500AA AF: 0.905 AC: 3988

ESP6500EA AF: 0.593 AC: 5101

ExAC AF: 0.647 AC: 78520

Asia WGS AF: 0.674 AC: 2345 AN: 3478

EpiCase AF: 0.583

EpiControl AF: 0.580

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Primary ciliary dyskinesia (2)
-	-	2	Primary ciliary dyskinesia 11 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.75
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.2	N
PhyloP100		3.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	7.9	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.23
ClinPred		0.0049	T
GERP RS		5.0
Varity_R		0.12
gMVP		0.38
Mutation Taster		=92/8	polymorphism (auto)

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: rs784133; hg19: chr6-116950833; COSMIC: COSV57636986;