rs10513155

chr5-13788777-C-Achr5-13788777-C-T

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.8586G>T(p.Leu2862Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,613,654 control chromosomes in the GnomAD database, including 58,738 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2862L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (4494 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54244 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.376

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=0.0048581064).
• BP6: Variant 5-13788777-C-A is Benign according to our data. Variant chr5-13788777-C-A is described in ClinVar as [Benign]. Clinvar id is 178745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13788777-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.8586G>T	p.Leu2862Phe	missense_variant	51/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.8586G>T	p.Leu2862Phe	missense_variant	51/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.8541G>T	p.Leu2847Phe	missense_variant	51/79			A1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36061 AN: 151964 Hom.: 4494 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.259

GnomAD3 exomes AF: 0.254 AC: 63945 AN: 251304 Hom.: 8430 AF XY: 0.258 AC XY: 35012 AN XY: 135828

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.220

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.280

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.269 AC: 393289 AN: 1461572 Hom.: 54244 Cov.: 35 AF XY: 0.268 AC XY: 194868 AN XY: 727084

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.334

Gnomad4 EAS exome AF: 0.181

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.221

Gnomad4 NFE exome AF: 0.279

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.237 AC: 36063 AN: 152082 Hom.: 4494 Cov.: 32 AF XY: 0.236 AC XY: 17539 AN XY: 74334

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.328

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.214

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.256

Alfa AF: 0.278 Hom.: 15499

Bravo AF: 0.239

TwinsUK AF: 0.275 AC: 1018

ALSPAC AF: 0.277 AC: 1068

ESP6500AA AF: 0.163 AC: 719

ESP6500EA AF: 0.289 AC: 2482

ExAC AF: 0.252 AC: 30634

Asia WGS AF: 0.212 AC: 738 AN: 3478

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	Leu2862Phe in exon 51 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 28.9% (2482/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs10513155). -
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	Dec 11, 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 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	8.4
Dann	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.96	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.097
Sift	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.018
MutPred		0.14		Gain of methylation at K2860 (P = 0.0635);
MPC		0.31
ClinPred		0.0049	T
GERP RS		4.0
Varity_R		0.057
gMVP		0.43

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

Other links and lift over

dbSNP: rs10513155; hg19: chr5-13788886; COSMIC: COSV54225134;