rs41267755

chr6-158999703-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_031924.8(RSPH3):c.-153C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,614,006 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (4 hom.)
• Consequence: RSPH3 NM_031924.8 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.410

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040013194).
• BP6: Variant 6-158999703-G-A is Benign according to our data. Variant chr6-158999703-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0019 (289/152338) while in subpopulation NFE AF= 0.00343 (233/68014). AF 95% confidence interval is 0.00306. There are 1 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPH3	NM_031924.8	c.-153C>T		5_prime_UTR_variant	1/8	ENST00000367069.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPH3	ENST00000367069.7	c.-153C>T		5_prime_UTR_variant	1/8	1	NM_031924.8	P1
RSPH3	ENST00000449822.5	c.-153C>T		5_prime_UTR_variant	1/6	2
TAGAP-AS1	ENST00000607391.5	n.236+9131G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152220 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00343

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00179 AC: 449 AN: 251032 Hom.: 0 AF XY: 0.00176 AC XY: 239 AN XY: 135672

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000741

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00314 AC: 4583 AN: 1461668 Hom.: 4 Cov.: 32 AF XY: 0.00298 AC XY: 2170 AN XY: 727118

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000937

Gnomad4 NFE exome AF: 0.00387

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74498

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00343

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00183

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00170 AC: 207

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00261

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 32 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 30, 2020

- -

RSPH3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.9
Dann	Benign	0.97
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.077
Sift	Uncertain	0.017	D
Sift4G	Benign	0.35	T
Polyphen		0.27	B
Vest4		0.12
MVP		0.088
MPC		0.36
ClinPred		0.019	T
GERP RS		-1.4
Varity_R		0.045
gMVP		0.037

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: rs41267755; hg19: chr6-159420735;