16-21000377-G-T

Variant names:

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

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>A​(p.His2044Asn) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH3 NM_001347886.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• 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=0.104436725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH3	NM_001347886.2	c.6130C>A	p.His2044Asn	missense_variant	Exon 43 of 62	ENST00000698260.1	NP_001334815.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH3	ENST00000698260.1	c.6130C>A	p.His2044Asn	missense_variant	Exon 43 of 62		NM_001347886.2	ENSP00000513632.1
DNAH3	ENST00000261383.3	c.6268C>A	p.His2090Asn	missense_variant	Exon 43 of 62	1		ENSP00000261383.3
DNAH3	ENST00000685858.1	c.6310C>A	p.His2104Asn	missense_variant	Exon 43 of 62			ENSP00000508756.1
DNAH3	ENST00000572640.5	n.2979C>A		non_coding_transcript_exon_variant	Exon 20 of 21	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Prostate cancer Uncertain:1

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Science for Life laboratory, Karolinska Institutet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.50
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.35	N
PhyloP100		0.70
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.088
Sift	Benign	0.68	T
Polyphen		0.028	B
Vest4		0.35
MutPred		0.24		Gain of ubiquitination at K2093 (P = 0.1106);
MVP		0.10
MPC		0.10
ClinPred		0.14	T
GERP RS		4.8
Varity_R		0.10
gMVP		0.27

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: COSV54504818;