rs556783606

Positions:

• chr6-158983780-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_031924.8(RSPH3):​c.374G>A​(p.Arg125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000353 in 1,602,886 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (4 hom.)
• Consequence: RSPH3 NM_031924.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:1
• Conservation: PhyloP100: 2.37

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00739491).
• BP6: Variant 6-158983780-C-T is Benign according to our data. Variant chr6-158983780-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475839.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000191 (29/152198) while in subpopulation SAS AF= 0.00519 (25/4816). AF 95% confidence interval is 0.00361. There are 1 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH3	NM_031924.8	c.374G>A	p.Arg125His	missense_variant	4/8	ENST00000367069.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH3	ENST00000367069.7	c.374G>A	p.Arg125His	missense_variant	4/8	1	NM_031924.8	P1
RSPH3	ENST00000449822.5	c.205-1092G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152080 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000788 AC: 198 AN: 251332 Hom.: 0 AF XY: 0.000994 AC XY: 135 AN XY: 135856

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00608

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000370 AC: 537 AN: 1450688 Hom.: 4 Cov.: 28 AF XY: 0.000507 AC XY: 366 AN XY: 722474

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000254

Gnomad4 OTH exome AF: 0.000484

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74408

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000647 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000848 AC: 103

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 32 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0090	D;T
Sift4G	Uncertain	0.016	D;D
Polyphen		0.51	.;P
Vest4		0.19
MVP		0.45
MPC		0.55
ClinPred		0.050	T
GERP RS		6.0
Varity_R		0.16
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs556783606; hg19: chr6-159404812; COSMIC: COSV51923707; COSMIC: COSV51923707;