rs1348689

Positions:

• chr5-13829690-G-A
• chr5-13829690-G-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.6264C>T​(p.Ala2088=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,612,658 control chromosomes in the GnomAD database, including 114,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2088A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.40 (12283 hom., cov: 33)
  • Exomes 𝑓: 0.37 (101984 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.832

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 5-13829690-G-A is Benign according to our data. Variant chr5-13829690-G-A is described in ClinVar as [Benign]. Clinvar id is 163145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13829690-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.832 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.6264C>T	p.Ala2088=	synonymous_variant	38/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.6264C>T	p.Ala2088=	synonymous_variant	38/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.6219C>T	p.Ala2073=	synonymous_variant	38/79			A1
DNAH5	ENST00000683090.1	n.1195C>T		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60495 AN: 151858 Hom.: 12267 Cov.: 33

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.400

GnomAD3 exomes AF: 0.385 AC: 96523 AN: 250998 Hom.: 19222 AF XY: 0.379 AC XY: 51433 AN XY: 135666

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.624

Gnomad SAS exome AF: 0.330

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.381

GnomAD4 exome AF: 0.371 AC: 541740 AN: 1460680 Hom.: 101984 Cov.: 37 AF XY: 0.369 AC XY: 267886 AN XY: 726712

Gnomad4 AFR exome AF: 0.459

Gnomad4 AMR exome AF: 0.378

Gnomad4 ASJ exome AF: 0.359

Gnomad4 EAS exome AF: 0.562

Gnomad4 SAS exome AF: 0.330

Gnomad4 FIN exome AF: 0.328

Gnomad4 NFE exome AF: 0.366

Gnomad4 OTH exome AF: 0.380

GnomAD4 genome AF: 0.398 AC: 60548 AN: 151978 Hom.: 12283 Cov.: 33 AF XY: 0.396 AC XY: 29383 AN XY: 74278

Gnomad4 AFR AF: 0.461

Gnomad4 AMR AF: 0.383

Gnomad4 ASJ AF: 0.366

Gnomad4 EAS AF: 0.610

Gnomad4 SAS AF: 0.331

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.397

Alfa AF: 0.362 Hom.: 6506

Bravo AF: 0.411

Asia WGS AF: 0.454 AC: 1578 AN: 3478

EpiCase AF: 0.370

EpiControl AF: 0.364

ClinVar

Significance: Benign

Submissions summary: Benign:10

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	Ala2088Ala in exon 38 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 45.6% (2011/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1348689). -
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, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 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	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Primary ciliary dyskinesia 3 Benign:2

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

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
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.8
DANN	Benign	0.64

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: rs1348689; hg19: chr5-13829799; COSMIC: COSV54225144;