16-20941519-C-A

Position:

• chr16-20941519-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001347886.2(DNAH3):​c.11398G>T​(p.Asp3800Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH3 NM_001347886.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

Genes affected

DNAH3 (HGNC:2949): (dynein axonemal heavy chain 3) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH3	NM_001347886.2	c.11398G>T	p.Asp3800Tyr	missense_variant	59/62	ENST00000698260.1	NP_001334815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH3	ENST00000698260.1	c.11398G>T	p.Asp3800Tyr	missense_variant	59/62		NM_001347886.2	ENSP00000513632.1
DNAH3	ENST00000261383.3	c.11536G>T	p.Asp3846Tyr	missense_variant	59/62	1		ENSP00000261383.3
DNAH3	ENST00000685858.1	c.11578G>T	p.Asp3860Tyr	missense_variant	59/62			ENSP00000508756.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.11536G>T (p.D3846Y) alteration is located in exon 59 (coding exon 59) of the DNAH3 gene. This alteration results from a G to T substitution at nucleotide position 11536, causing the aspartic acid (D) at amino acid position 3846 to be replaced by a tyrosine (Y). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.57		Loss of disorder (P = 0.0278);
MVP		0.17
MPC		0.53
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2083808460; hg19: chr16-20952841;