Genetic Variant DNAH14:p.Leu828Met (chr1-225079264-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001367479.1(DNAH14):c.2482C>A(p.Leu828Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000388 in 1,547,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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. L828V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

DNAH14
NM_001367479.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.359

Publications

20 publications found

Variant links:

Genes affected

DNAH14 (HGNC:2945): (dynein axonemal heavy chain 14) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. Two major classes of dyneins, axonemal and cytoplasmic, have been identified. DNAH14 is an axonemal dynein heavy chain (DHC) (Vaughan et al., 1996 [PubMed 8812413]).[supplied by OMIM, Mar 2008]

DNAH14 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

DNAH14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056978136).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367479.1. 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
	DNAH14	NM_001367479.1	MANE Select	c.2482C>A	p.Leu828Met	missense	Exon 18 of 86	NP_001354408.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAH14	ENST00000682510.1	MANE Select	c.2482C>A	p.Leu828Met	missense	Exon 18 of 86	ENSP00000508305.1
DNAH14	ENST00000430092.5	TSL:5	c.2482C>A	p.Leu828Met	missense	Exon 18 of 84	ENSP00000414402.1
DNAH14	ENST00000439375.6	TSL:5	c.2482C>A	p.Leu828Met	missense	Exon 17 of 83	ENSP00000392061.2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000358

AC:

AN:

1395654

Hom.:

Cov.:

AF XY:

0.00000436

AC XY:

AN XY:

688230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31322

American (AMR)

AF:

0.00

AC:

AN:

34598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25120

East Asian (EAS)

AF:

0.00

AC:

AN:

35664

South Asian (SAS)

AF:

0.00

AC:

AN:

78188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5374

European-Non Finnish (NFE)

AF:

0.00000464

AC:

AN:

1078294

Other (OTH)

AF:

0.00

AC:

AN:

57840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

AF:

0.00000658

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41310

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

17111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0015

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.25

M_CAP

Benign

0.011

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

PhyloP100

0.36

PrimateAI

Benign

0.47

PROVEAN

Benign

0.010

REVEL

Benign

0.024

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.052

Polyphen

0.0010

Vest4

0.11

MutPred

0.38

Loss of catalytic residue at L828 (P = 0.0168)

MVP

0.055

ClinPred

0.13

GERP RS

2.4

Varity_R

0.089

Mutation Taster

=94/6

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