Genetic Variant DNAH3:p.Phe2265Leu (chr16-20987398-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001347886.2(DNAH3):c.6795C>G(p.Phe2265Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F2265F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DNAH3
NM_001347886.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.36

Publications

0 publications found

Variant links:

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

DNAH3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	NM_001347886.2	MANE Select	c.6795C>G	p.Phe2265Leu	missense	Exon 47 of 62	NP_001334815.1
	DNAH3	NM_017539.2		c.6933C>G	p.Phe2311Leu	missense	Exon 47 of 62	NP_060009.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAH3	ENST00000698260.1	MANE Select	c.6795C>G	p.Phe2265Leu	missense	Exon 47 of 62	ENSP00000513632.1
DNAH3	ENST00000261383.3	TSL:1	c.6933C>G	p.Phe2311Leu	missense	Exon 47 of 62	ENSP00000261383.3
DNAH3	ENST00000685858.1		c.6975C>G	p.Phe2325Leu	missense	Exon 47 of 62	ENSP00000508756.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

3.9

PhyloP100

1.4

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

Polyphen

1.0

Vest4

0.94

MutPred

0.73

Gain of catalytic residue at F2311 (P = 0.1258)

MVP

0.29

MPC

0.53

ClinPred

1.0

GERP RS

3.7

Varity_R

0.88

gMVP

0.59

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over