dbSNP rs375791690: DNAH14:p.Pro168Thr (chr1-224967434-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.502C>A(p.Pro168Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. P168S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

DNAH14
NM_001367479.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.329

Publications

0 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=0.058718264).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAH14	NM_001367479.1	MANE Select	c.502C>A	p.Pro168Thr	missense	Exon 6 of 86	NP_001354408.1
DNAH14	NM_001145154.3		c.502C>A	p.Pro168Thr	missense	Exon 6 of 11	NP_001138626.1
DNAH14	NM_001349911.2		c.502C>A	p.Pro168Thr	missense	Exon 6 of 11	NP_001336840.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAH14	ENST00000682510.1	MANE Select	c.502C>A	p.Pro168Thr	missense	Exon 6 of 86	ENSP00000508305.1
DNAH14	ENST00000400952.7	TSL:1	c.502C>A	p.Pro168Thr	missense	Exon 6 of 11	ENSP00000383737.3
DNAH14	ENST00000366849.5	TSL:1	c.502C>A	p.Pro168Thr	missense	Exon 6 of 11	ENSP00000355814.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.23e-7

AC:

AN:

1383294

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686592

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29156

American (AMR)

AF:

0.00

AC:

AN:

28704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23360

East Asian (EAS)

AF:

0.00

AC:

AN:

36752

South Asian (SAS)

AF:

0.0000142

AC:

AN:

70620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5454

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081142

Other (OTH)

AF:

0.00

AC:

AN:

56814

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.1

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.017

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.69

M_CAP

Benign

0.011

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.98

PhyloP100

-0.33

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.2

REVEL

Benign

0.023

Sift

Benign

0.073

Sift4G

Uncertain

0.011

Polyphen

0.027

Vest4

0.37

MutPred

0.37

Gain of helix (P = 0.0143)

MVP

0.10

MPC

0.094

ClinPred

0.045

GERP RS

-2.4

Varity_R

0.058

gMVP

0.058

Mutation Taster

=99/1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over