16-20933462-C-G

Variant names:

• chr16-20933462-C-G
• NM_001347886.2:c.11905G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001347886.2(DNAH3):​c.11905G>C​(p.Ala3969Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAH3 NM_001347886.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH3	NM_001347886.2	c.11905G>C	p.Ala3969Pro	missense_variant	Exon 62 of 62	ENST00000698260.1	NP_001334815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH3	ENST00000698260.1	c.11905G>C	p.Ala3969Pro	missense_variant	Exon 62 of 62		NM_001347886.2	ENSP00000513632.1
DNAH3	ENST00000261383.3	c.12043G>C	p.Ala4015Pro	missense_variant	Exon 62 of 62	1		ENSP00000261383.3
DNAH3	ENST00000685858.1	c.12085G>C	p.Ala4029Pro	missense_variant	Exon 62 of 62			ENSP00000508756.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459900 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

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 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.12043G>C (p.A4015P) alteration is located in exon 62 (coding exon 62) of the DNAH3 gene. This alteration results from a G to C substitution at nucleotide position 12043, causing the alanine (A) at amino acid position 4015 to be replaced by a proline (P). 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	0.95
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.79		Gain of disorder (P = 0.0448);
MVP		0.24
MPC		0.54
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-20944784;