rs115004914

Positions:

chr5-13900212-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001369.3(DNAH5):c.2253C>A(p.Asn751Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,612,604 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 130 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.655

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:

ENSG00000251423 (HGNC:):

ENSG00000251423 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028903186).

BP6

Variant 5-13900212-G-T is Benign according to our data. Variant chr5-13900212-G-T is described in ClinVar as [Benign]. Clinvar id is 178754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13900212-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00517 (787/152296) while in subpopulation SAS AF= 0.0332 (160/4824). AF 95% confidence interval is 0.029. There are 2 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. Median coverage is 32. 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	Protein	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.2253C>A	p.Asn751Lys	missense_variant	15/79	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.2253C>A	p.Asn751Lys	missense_variant	15/79	1	NM_001369.3	ENSP00000265104.4	Q8TE73
DNAH5	ENST00000681290.1 linkuse as main transcript	c.2208C>A	p.Asn736Lys	missense_variant	15/79			ENSP00000505288.1	A0A7P0Z455
ENSG00000251423	ENST00000503244.2 linkuse as main transcript	n.3088G>T		non_coding_transcript_exon_variant	3/3	4
ENSG00000251423	ENST00000637153.1 linkuse as main transcript	n.3048G>T		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes

AF:

0.00520

AC:

792

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0338

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00557

Gnomad OTH

AF:

0.00623

GnomAD3 exomes

AF:

0.00972

AC:

2439

AN:

250898

Hom.:

AF XY:

0.0113

AC XY:

1534

AN XY:

135646

show subpopulations

Gnomad AFR exome

AF:

0.000557

Gnomad AMR exome

AF:

0.00526

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.00212

Gnomad SAS exome

AF:

0.0387

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.00650

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.00728

AC:

10631

AN:

1460308

Hom.:

130

Cov.:

AF XY:

0.00847

AC XY:

6155

AN XY:

726610

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.00541

Gnomad4 ASJ exome

AF:

0.0136

Gnomad4 EAS exome

AF:

0.00113

Gnomad4 SAS exome

AF:

0.0391

Gnomad4 FIN exome

AF:

0.00300

Gnomad4 NFE exome

AF:

0.00505

Gnomad4 OTH exome

AF:

0.00923

GnomAD4 genome

AF:

0.00517

AC:

787

AN:

152296

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

428

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00765

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.00231

Gnomad4 SAS

AF:

0.0332

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00557

Gnomad4 OTH

AF:

0.00569

Alfa

AF:

0.00645

Hom.:

Bravo

AF:

0.00465

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.0101

AC:

1232

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.00638

EpiControl

AF:

0.00711

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2020	This variant is associated with the following publications: (PMID: 31213628) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DNAH5: BP4, BS1, BS2 -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2016	p.Asn751Lys in exon 15 of DNAH5: This variant is not expected to have clinical s ignificance because it has been identified in 3.8% (635/16496) of South Asian ch romosomes, including 18 homozygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs115004914). -

Primary ciliary dyskinesia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 09, 2015	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. -

Primary ciliary dyskinesia 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.045

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.085

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.59

REVEL

Benign

0.084

Sift

Benign

0.98

Polyphen

0.0

Vest4

0.16

MutPred

0.58

Gain of disorder (P = 0.06);

MPC

0.34

ClinPred

0.011

GERP RS

1.3

Varity_R

0.056

gMVP

0.21

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

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