16-20933475-G-C

Variant names:

• chr16-20933475-G-C
• NM_001347886.2:c.11892C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001347886.2(DNAH3):​c.11892C>G​(p.Asn3964Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAH3 NM_001347886.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.488

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0649862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH3	NM_001347886.2	c.11892C>G	p.Asn3964Lys	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.11892C>G	p.Asn3964Lys	missense_variant	Exon 62 of 62		NM_001347886.2	ENSP00000513632.1
DNAH3	ENST00000261383.3	c.12030C>G	p.Asn4010Lys	missense_variant	Exon 62 of 62	1		ENSP00000261383.3
DNAH3	ENST00000685858.1	c.12072C>G	p.Asn4024Lys	missense_variant	Exon 62 of 62			ENSP00000508756.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.12030C>G (p.N4010K) alteration is located in exon 62 (coding exon 62) of the DNAH3 gene. This alteration results from a C to G substitution at nucleotide position 12030, causing the asparagine (N) at amino acid position 4010 to be replaced by a lysine (K). 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	Benign	0.076
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.70
DANN	Benign	0.92
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.10	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-2.2	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.082
Sift	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.056
MutPred		0.44		Gain of ubiquitination at N4010 (P = 0.0082);
MVP		0.030
MPC		0.11
ClinPred		0.18	T
GERP RS		2.0
Varity_R		0.072
gMVP		0.26

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: chr16-20944797;