chr5-13865871-T-C

Position:

• chr5-13865871-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001369.3(DNAH5):​c.4152A>G​(p.Thr1384Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,606,262 control chromosomes in the GnomAD database, including 178,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18244 hom., cov: 32)
  • Exomes 𝑓: 0.47 (160018 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0420

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 5-13865871-T-C is Benign according to our data. Variant chr5-13865871-T-C is described in ClinVar as [Benign]. Clinvar id is 178751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13865871-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.042 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.4152A>G	p.Thr1384Thr	synonymous_variant	27/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.4152A>G	p.Thr1384Thr	synonymous_variant	27/79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.4107A>G	p.Thr1369Thr	synonymous_variant	27/79			ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.253+5316T>C		intron_variant		4
ENSG00000251423	ENST00000637153.1	n.213+5356T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73749 AN: 151872 Hom.: 18216 Cov.: 32

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.465

GnomAD3 exomes AF: 0.449 AC: 112264 AN: 249798 Hom.: 26237 AF XY: 0.455 AC XY: 61603 AN XY: 135316

Gnomad AFR exome AF: 0.572

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.398

Gnomad EAS exome AF: 0.322

Gnomad SAS exome AF: 0.538

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.465 AC: 676687 AN: 1454272 Hom.: 160018 Cov.: 33 AF XY: 0.467 AC XY: 337688 AN XY: 723858

Gnomad4 AFR exome AF: 0.580

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.324

Gnomad4 SAS exome AF: 0.530

Gnomad4 FIN exome AF: 0.499

Gnomad4 NFE exome AF: 0.469

Gnomad4 OTH exome AF: 0.456

GnomAD4 genome AF: 0.486 AC: 73840 AN: 151990 Hom.: 18244 Cov.: 32 AF XY: 0.483 AC XY: 35885 AN XY: 74316

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.379

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.524

Gnomad4 FIN AF: 0.508

Gnomad4 NFE AF: 0.472

Gnomad4 OTH AF: 0.468

Alfa AF: 0.460 Hom.: 29803

Bravo AF: 0.474

Asia WGS AF: 0.455 AC: 1584 AN: 3476

EpiCase AF: 0.454

EpiControl AF: 0.452

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

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 specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr1384Thr in exon 27 of DNAH5: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 46.7% (4011/8592) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs7703349). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.1
DANN	Benign	0.61

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: rs7703349; hg19: chr5-13865980; COSMIC: COSV54212563;