16-21000377-G-A

Variant names:

• chr16-21000377-G-A
• rs193921090
• NM_001347886.2:c.6130C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001347886.2(DNAH3):​c.6130C>T​(p.His2044Tyr) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2044N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH3 NM_001347886.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.700
• Publications: 0 publications found

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]

DNAH3 Gene-Disease associations (from GenCC):

• male infertility

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20040789).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347886.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	NM_001347886.2	MANE Select	c.6130C>T	p.His2044Tyr	missense	Exon 43 of 62	NP_001334815.1	A0A8V8TLI9
	DNAH3	NM_017539.2		c.6268C>T	p.His2090Tyr	missense	Exon 43 of 62	NP_060009.1	Q8TD57-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	ENST00000698260.1	MANE Select	c.6130C>T	p.His2044Tyr	missense	Exon 43 of 62	ENSP00000513632.1	A0A8V8TLI9
	DNAH3	ENST00000261383.3	TSL:1	c.6268C>T	p.His2090Tyr	missense	Exon 43 of 62	ENSP00000261383.3	Q8TD57-1
	DNAH3	ENST00000685858.1		c.6310C>T	p.His2104Tyr	missense	Exon 43 of 62	ENSP00000508756.1	A0A8I5KSE2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.70
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.097
Sift	Uncertain	0.026	D
Polyphen		0.25	B
Vest4		0.29
MutPred		0.34		Gain of ubiquitination at K2093 (P = 0.1278)
MVP		0.20
MPC		0.11
ClinPred		0.50	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.30

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

Other links and lift over

dbSNP: rs193921090; hg19: chr16-21011699; COSMIC: COSV54514883;