19-45804391-T-A

Variant names:

• chr19-45804391-T-A
• rs1970511968
• NM_030785.4:c.1514A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030785.4(RSPH6A):​c.1514A>T​(p.Glu505Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RSPH6A NM_030785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.28

Genes affected

RSPH6A (HGNC:14241): (radial spoke head 6 homolog A) The protein encoded by this gene is similar to a sea urchin radial spoke head protein. Radial spoke protein complexes form part of the axoneme of eukaryotic flagella and are located between the axoneme's outer ring of doublet microtubules and central pair of microtubules. In Chlamydomonas, radial spoke proteins are thought to regulate the activity of dynein and the symmetry of flagellar bending patterns. This gene maps to a region of chromosome 19 that is linked to primary ciliary dyskinesia-2 (CILD2). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH6A	NM_030785.4	c.1514A>T	p.Glu505Val	missense_variant	Exon 3 of 6	ENST00000221538.8	NP_110412.1
RSPH6A	XM_011527351.3	c.1514A>T	p.Glu505Val	missense_variant	Exon 3 of 6		XP_011525653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH6A	ENST00000221538.8	c.1514A>T	p.Glu505Val	missense_variant	Exon 3 of 6	1	NM_030785.4	ENSP00000221538.2
RSPH6A	ENST00000597055.1	c.1514A>T	p.Glu505Val	missense_variant	Exon 3 of 6	1		ENSP00000472630.1
RSPH6A	ENST00000600188.5	c.722A>T	p.Glu241Val	missense_variant	Exon 2 of 5	2		ENSP00000471559.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1514A>T (p.E505V) alteration is located in exon 3 (coding exon 3) of the RSPH6A gene. This alteration results from a A to T substitution at nucleotide position 1514, causing the glutamic acid (E) at amino acid position 505 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.2	D;.;.
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D;.;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.51
MutPred		0.54		Loss of disorder (P = 0.0266);.;Loss of disorder (P = 0.0266);
MVP		0.27
MPC		0.52
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.70
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1970511968; hg19: chr19-46307649;