NM_031924.8:c.992A>C

Variant names:

• chr6-158977803-T-G
• rs78116655
• NM_031924.8:c.992A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031924.8(RSPH3):​c.992A>C​(p.His331Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,614,150 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H331R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0082 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (18 hom.)
• Consequence: RSPH3 NM_031924.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.82
• Publications: 0 publications found

Genes affected

RSPH3 (HGNC:21054): (radial spoke head 3) The protein encoded by this gene acts as a protein kinase A anchoring protein. Mutations in this gene cause primary ciliary dyskinesia; a disorder characterized by defects of the axoneme in motile cilia and sperm flagella. The homolog of this gene was first identified in the blue-green algae Chlamydomonas as encoding a radial spoke protein that formed a structural component of motile cilia and flagella. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

RSPH3 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 32

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003074646).
• BP6: Variant 6-158977803-T-G is Benign according to our data. Variant chr6-158977803-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0082 (1249/152330) while in subpopulation AFR AF = 0.0284 (1180/41572). AF 95% confidence interval is 0.027. There are 22 homozygotes in GnomAd4. There are 629 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031924.8. 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
	RSPH3	NM_031924.8	MANE Select	c.992A>C	p.His331Pro	missense	Exon 8 of 8	NP_114130.4
	RSPH3	NM_001346418.1		c.1130A>C	p.His377Pro	missense	Exon 6 of 6	NP_001333347.1	Q86UC2-2
	RSPH3	NR_144434.1		n.1629A>C		non_coding_transcript_exon	Exon 8 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.992A>C	p.His331Pro	missense	Exon 8 of 8	ENSP00000356036.1	A0A0C4DFU3
	RSPH3	ENST00000884885.1		c.824A>C	p.His275Pro	missense	Exon 7 of 7	ENSP00000554944.1
	RSPH3	ENST00000449822.6	TSL:2	c.704A>C	p.His235Pro	missense	Exon 6 of 6	ENSP00000393195.1	A0A0C4DG29

Frequencies

GnomAD3 genomes AF: 0.00819 AC: 1247 AN: 152212 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

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: 0.0000735

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00232 AC: 581 AN: 250852 AF XY: 0.00164

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000830 AC: 1213 AN: 1461820 Hom.: 18 Cov.: 32 AF XY: 0.000719 AC XY: 523 AN XY: 727216

African (AFR) AF: 0.0296 AC: 992 AN: 33474

American (AMR) AF: 0.00148 AC: 66 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111996

Other (OTH) AF: 0.00172 AC: 104 AN: 60394

GnomAD4 genome AF: 0.00820 AC: 1249 AN: 152330 Hom.: 22 Cov.: 32 AF XY: 0.00844 AC XY: 629 AN XY: 74492

African (AFR) AF: 0.0284 AC: 1180 AN: 41572

American (AMR) AF: 0.00340 AC: 52 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00301 Hom.: 21

Bravo AF: 0.00957

ESP6500AA AF: 0.0340 AC: 150

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00288 AC: 350

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Primary ciliary dyskinesia 32 (2)
-	-	1	RSPH3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0030
DANN	Benign	0.24
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		-3.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.018
Sift	Benign	0.16	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.067
MPC		0.46
ClinPred		0.0038	T
GERP RS		-5.3
Varity_R		0.097
gMVP		0.39
Mutation Taster		=99/1	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: rs78116655; hg19: chr6-159398835;