19-45795984-T-G

Variant names:

• chr19-45795984-T-G
• rs1460505549
• NM_030785.4:c.2039A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_030785.4(RSPH6A):​c.2039A>C​(p.Asp680Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RSPH6A NM_030785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.50

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPH6A	NM_030785.4	c.2039A>C	p.Asp680Ala	missense_variant	Exon 6 of 6	ENST00000221538.8	NP_110412.1
RSPH6A	XM_011527351.3	c.*114A>C		downstream_gene_variant			XP_011525653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPH6A	ENST00000221538.8	c.2039A>C	p.Asp680Ala	missense_variant	Exon 6 of 6	1	NM_030785.4	ENSP00000221538.2
RSPH6A	ENST00000597055	c.*4A>C		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000472630.1
RSPH6A	ENST00000600188.5	c.1247A>C	p.Asp416Ala	missense_variant	Exon 5 of 5	2		ENSP00000471559.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2039A>C (p.D680A) alteration is located in exon 6 (coding exon 6) of the RSPH6A gene. This alteration results from a A to C substitution at nucleotide position 2039, causing the aspartic acid (D) at amino acid position 680 to be replaced by an alanine (A). 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	0.96
BayesDel_addAF	Benign	-0.0079	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.2	D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;.
Vest4		0.75
MVP		0.41
MPC		0.54
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.79
gMVP		0.81

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: rs1460505549; hg19: chr19-46299242;