rs1348689

Variant names:

• chr5-13829690-G-A
• rs1348689
• NM_001369.3:c.6264C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-13829690-G-A
• chr5-13829690-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001369.3(DNAH5):​c.6264C>T​(p.Ala2088Ala) 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:11
• Conservation: PhyloP100: -0.832
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 163145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.6264C>T	p.Ala2088Ala	synonymous_variant	Exon 38 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.6264C>T	p.Ala2088Ala	synonymous_variant	Exon 38 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.6219C>T	p.Ala2073Ala	synonymous_variant	Exon 38 of 79			ENSP00000505288.1
DNAH5	ENST00000683090.1	n.1195C>T		non_coding_transcript_exon_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.385 AC: 96523 AN: 250998 AF XY: 0.379

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 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

African (AFR) AF: 0.459 AC: 15365 AN: 33452

American (AMR) AF: 0.378 AC: 16884 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 9392 AN: 26134

East Asian (EAS) AF: 0.562 AC: 22319 AN: 39690

South Asian (SAS) AF: 0.330 AC: 28419 AN: 86246

European-Finnish (FIN) AF: 0.328 AC: 17488 AN: 53396

Middle Eastern (MID) AF: 0.335 AC: 1933 AN: 5762

European-Non Finnish (NFE) AF: 0.366 AC: 407021 AN: 1110926

Other (OTH) AF: 0.380 AC: 22919 AN: 60364

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

African (AFR) AF: 0.461 AC: 19099 AN: 41420

American (AMR) AF: 0.383 AC: 5855 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1270 AN: 3470

East Asian (EAS) AF: 0.610 AC: 3151 AN: 5166

South Asian (SAS) AF: 0.331 AC: 1590 AN: 4806

European-Finnish (FIN) AF: 0.317 AC: 3351 AN: 10556

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24884 AN: 67970

Other (OTH) AF: 0.397 AC: 837 AN: 2108

Alfa AF: 0.364 Hom.: 7318

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 10, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 3 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.8
DANN	Benign	0.64
PhyloP100		-0.83
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

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