chr5-13914634-A-T

Position:

chr5-13914634-A-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001369.3(DNAH5):c.1206T>A(p.Asn402Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00231 in 1,612,854 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 7 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:6

Conservation

PhyloP100: 0.685

Variant links:

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

DNAH5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13478532).

BP6

Variant 5-13914634-A-T is Benign according to our data. Variant chr5-13914634-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188080.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5, Benign=1}. Variant chr5-13914634-A-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00239 (3484/1460690) while in subpopulation MID AF= 0.0089 (51/5728). AF 95% confidence interval is 0.00696. There are 7 homozygotes in gnomad4_exome. There are 1730 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.1206T>A	p.Asn402Lys	missense_variant	10/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.1206T>A	p.Asn402Lys	missense_variant	10/79	1	NM_001369.3	P4

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00258

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00159

AC:

399

AN:

250848

Hom.:

AF XY:

0.00164

AC XY:

222

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.000509

Gnomad NFE exome

AF:

0.00269

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00239

AC:

3484

AN:

1460690

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

1730

AN XY:

726694

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.000460

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000789

Gnomad4 FIN exome

AF:

0.000450

Gnomad4 NFE exome

AF:

0.00283

Gnomad4 OTH exome

AF:

0.00196

GnomAD4 genome

AF:

0.00162

AC:

247

AN:

152164

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00258

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00206

Hom.:

Bravo

AF:

0.00189

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00149

AC:

181

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DNAH5: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2014	- -

Primary ciliary dyskinesia 3

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Primary ciliary dyskinesia

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 28, 2024	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 24, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Asn402Lys var iant in DNAH5 was identified in 1 heterozygous individual with primary ciliary d yskinesia (Cozzolino 2009). It has also been identified in 0.23% (153/66670) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs140782270). Computational prediction tools and conservat ion analysis do not provide strong support for or against an impact to the prote in. In summary, while the clinical significance of the p.Asn402Lys variant is un certain, its frequency suggests that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.32

MutationAssessor

Pathogenic

3.7

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

Polyphen

1.0

Vest4

0.88

MutPred

0.79

Gain of MoRF binding (P = 0.0339);

MVP

0.77

MPC

0.38

ClinPred

0.084

GERP RS

3.1

Varity_R

0.94

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over