rs339445

Positions:

• chr5-13944403-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.36T>G​(p.His12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.938 in 1,613,616 control chromosomes in the GnomAD database, including 710,864 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65399 hom., cov: 31)
  • Exomes 𝑓: 0.94 (645465 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.762

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.602909E-7).
• BP6: Variant 5-13944403-A-C is Benign according to our data. Variant chr5-13944403-A-C is described in ClinVar as [Benign]. Clinvar id is 178760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13944403-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.36T>G	p.His12Gln	missense_variant	1/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.36T>G	p.His12Gln	missense_variant	1/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.13-13159T>G		intron_variant				A1

Frequencies

GnomAD3 genomes AF: 0.926 AC: 140894 AN: 152092 Hom.: 65356 Cov.: 31

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.957

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.919

Gnomad FIN AF: 0.979

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.942

Gnomad OTH AF: 0.924

GnomAD3 exomes AF: 0.936 AC: 234735 AN: 250786 Hom.: 110008 AF XY: 0.935 AC XY: 126752 AN XY: 135564

Gnomad AFR exome AF: 0.884

Gnomad AMR exome AF: 0.956

Gnomad ASJ exome AF: 0.953

Gnomad EAS exome AF: 0.881

Gnomad SAS exome AF: 0.917

Gnomad FIN exome AF: 0.977

Gnomad NFE exome AF: 0.942

Gnomad OTH exome AF: 0.930

GnomAD4 exome AF: 0.940 AC: 1373106 AN: 1461406 Hom.: 645465 Cov.: 50 AF XY: 0.939 AC XY: 682495 AN XY: 727044

Gnomad4 AFR exome AF: 0.881

Gnomad4 AMR exome AF: 0.954

Gnomad4 ASJ exome AF: 0.953

Gnomad4 EAS exome AF: 0.900

Gnomad4 SAS exome AF: 0.914

Gnomad4 FIN exome AF: 0.978

Gnomad4 NFE exome AF: 0.943

Gnomad4 OTH exome AF: 0.928

GnomAD4 genome AF: 0.926 AC: 140995 AN: 152210 Hom.: 65399 Cov.: 31 AF XY: 0.927 AC XY: 69016 AN XY: 74420

Gnomad4 AFR AF: 0.885

Gnomad4 AMR AF: 0.936

Gnomad4 ASJ AF: 0.957

Gnomad4 EAS AF: 0.886

Gnomad4 SAS AF: 0.918

Gnomad4 FIN AF: 0.979

Gnomad4 NFE AF: 0.942

Gnomad4 OTH AF: 0.925

Alfa AF: 0.936 Hom.: 165288

Bravo AF: 0.922

TwinsUK AF: 0.947 AC: 3511

ALSPAC AF: 0.948 AC: 3652

ESP6500AA AF: 0.894 AC: 3937

ESP6500EA AF: 0.942 AC: 8101

ExAC AF: 0.936 AC: 113608

Asia WGS AF: 0.907 AC: 3154 AN: 3478

EpiCase AF: 0.934

EpiControl AF: 0.935

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	His12Gln in exon 1 of DNAH5: This variant is not expected to have clinical signi ficance because it has been identified in 10.6% (469/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs339445). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary ciliary dyskinesia Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 26, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Primary ciliary dyskinesia 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, 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 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	18
DANN	Benign	0.63
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.1	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.091
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.041
MutPred		0.077		Gain of helix (P = 0.0425);
MPC		0.094
ClinPred		0.0062	T
GERP RS		3.8
Varity_R		0.053
gMVP		0.14

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

Other links and lift over

dbSNP: rs339445; hg19: chr5-13944512; COSMIC: COSV54244960;