6-158999769-C-T

Variant names:

• chr6-158999769-C-T
• rs753412130
• NM_031924.8:c.-219G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001346418.1(RSPH3):​c.208G>A​(p.Ala70Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A70V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RSPH3 NM_001346418.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.986
• Publications: 1 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04755333).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346418.1. 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.-219G>A		5_prime_UTR	Exon 1 of 8	NP_114130.4
	RSPH3	NM_001346418.1		c.208G>A	p.Ala70Thr	missense	Exon 1 of 6	NP_001333347.1	Q86UC2-2
	RSPH3	NR_144434.1		n.419G>A		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPH3	ENST00000367069.7	TSL:1 MANE Select	c.-219G>A		5_prime_UTR	Exon 1 of 8	ENSP00000356036.1	A0A0C4DFU3
	RSPH3	ENST00000884885.1		c.-219G>A		5_prime_UTR	Exon 1 of 7	ENSP00000554944.1
	RSPH3	ENST00000449822.6	TSL:2	c.-219G>A		5_prime_UTR	Exon 1 of 6	ENSP00000393195.1	A0A0C4DG29

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248524 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458632 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725076

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000898 AC: 4 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 85996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109830

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia 32 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.1
DANN	Benign	0.95
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.99
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.020
Sift	Benign	0.21	T
Sift4G	Benign	0.42	T
PromoterAI		-0.036	Neutral
Varity_R		0.047
gMVP		0.027
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs753412130;

hg19: chr6-159420801;