rs61750777

Positions:

• chr6-158999516-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031924.8(RSPH3):​c.35C>T​(p.Ala12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,571,204 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (102 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (108 hom.)
• Consequence: RSPH3 NM_031924.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.638

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]

TAGAP-AS1 (HGNC:55239): (TAGAP antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020791888).
• BP6: Variant 6-158999516-G-A is Benign according to our data. Variant chr6-158999516-G-A is described in ClinVar as [Benign]. Clinvar id is 475832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSPH3	NM_031924.8	c.35C>T	p.Ala12Val	missense_variant	1/8	ENST00000367069.7	NP_114130.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSPH3	ENST00000367069.7	c.35C>T	p.Ala12Val	missense_variant	1/8	1	NM_031924.8	ENSP00000356036	P1
RSPH3	ENST00000449822.5	c.35C>T	p.Ala12Val	missense_variant	1/6	2		ENSP00000393195
TAGAP-AS1	ENST00000607391.5	n.236+8944G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3224 AN: 152080 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.0738

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.00654 AC: 1475 AN: 225590 Hom.: 46 AF XY: 0.00490 AC XY: 591 AN XY: 120588

Gnomad AFR exome AF: 0.0766

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.000266

Gnomad EAS exome AF: 0.00414

Gnomad SAS exome AF: 0.0000777

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00231 AC: 3281 AN: 1419006 Hom.: 108 Cov.: 31 AF XY: 0.00198 AC XY: 1383 AN XY: 699656

Gnomad4 AFR exome AF: 0.0784

Gnomad4 AMR exome AF: 0.00456

Gnomad4 ASJ exome AF: 0.000423

Gnomad4 EAS exome AF: 0.00217

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000930

Gnomad4 OTH exome AF: 0.00506

GnomAD4 genome AF: 0.0212 AC: 3228 AN: 152198 Hom.: 102 Cov.: 32 AF XY: 0.0206 AC XY: 1530 AN XY: 74410

Gnomad4 AFR AF: 0.0736

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00421 Hom.: 15

Bravo AF: 0.0232

ESP6500AA AF: 0.0697 AC: 307

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00692 AC: 839

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 32 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.66	T;T;T
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.055
Sift	Uncertain	0.026	D;D;D
Sift4G	Benign	0.075	T;T;D
Polyphen		0.055	.;.;B
Vest4		0.058
MVP		0.13
MPC		0.31
ClinPred		0.036	T
GERP RS		4.4
Varity_R		0.12
gMVP		0.086

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

Publications

LitVar

Other links and lift over

dbSNP: rs61750777; hg19: chr6-159420548;