chr5-13754285-C-T

Variant names:

• chr5-13754285-C-T
• rs2401809
• NM_001369.3:c.10473G>A

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.10473G>A​(p.Thr3491Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,622 control chromosomes in the GnomAD database, including 104,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9572 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95037 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.38

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=-0.68).
• BP6: Variant 5-13754285-C-T is Benign according to our data. Variant chr5-13754285-C-T is described in ClinVar as [Benign]. Clinvar id is 163136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13754285-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.10473G>A	p.Thr3491Thr	synonymous_variant	Exon 62 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.10473G>A	p.Thr3491Thr	synonymous_variant	Exon 62 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.10428G>A	p.Thr3476Thr	synonymous_variant	Exon 62 of 79			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53051 AN: 151864 Hom.: 9571 Cov.: 32

Gnomad AFR AF: 0.340

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.354

GnomAD3 exomes AF: 0.347 AC: 87171 AN: 251064 Hom.: 16007 AF XY: 0.356 AC XY: 48244 AN XY: 135676

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.310

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.462

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.357 AC: 522055 AN: 1461638 Hom.: 95037 Cov.: 40 AF XY: 0.361 AC XY: 262358 AN XY: 727146

Gnomad4 AFR exome AF: 0.337

Gnomad4 AMR exome AF: 0.310

Gnomad4 ASJ exome AF: 0.338

Gnomad4 EAS exome AF: 0.134

Gnomad4 SAS exome AF: 0.453

Gnomad4 FIN exome AF: 0.379

Gnomad4 NFE exome AF: 0.360

Gnomad4 OTH exome AF: 0.355

GnomAD4 genome AF: 0.349 AC: 53074 AN: 151984 Hom.: 9572 Cov.: 32 AF XY: 0.352 AC XY: 26140 AN XY: 74286

Gnomad4 AFR AF: 0.339

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.335

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.356

Alfa AF: 0.339 Hom.: 5102

Bravo AF: 0.337

Asia WGS AF: 0.345 AC: 1197 AN: 3478

EpiCase AF: 0.361

EpiControl AF: 0.359

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

Nov 26, 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. -

Primary ciliary dyskinesia 3 Benign:3

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr3491Thr in exon 62 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 36.4% (3128/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2401809). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Dec 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.066
DANN	Benign	0.48

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: rs2401809; hg19: chr5-13754394; COSMIC: COSV54228709;