chr5-13780882-C-T

Position:

chr5-13780882-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001369.3(DNAH5):c.8898G>A(p.Thr2966=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,613,708 control chromosomes in the GnomAD database, including 696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 55 hom., cov: 32)

Exomes 𝑓: 0.028 ( 641 hom. )

Consequence

DNAH5
NM_001369.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.59

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 5-13780882-C-T is Benign according to our data. Variant chr5-13780882-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 163138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13780882-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.59 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0226 (3441/152288) while in subpopulation NFE AF= 0.0308 (2092/68028). AF 95% confidence interval is 0.0297. There are 55 homozygotes in gnomad4. There are 1755 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.8898G>A	p.Thr2966=	synonymous_variant	53/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.8898G>A	p.Thr2966=	synonymous_variant	53/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.8853G>A	p.Thr2951=	synonymous_variant	53/79			ENSP00000505288	A1

Frequencies

GnomAD3 genomes

AF:

0.0226

AC:

3442

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00528

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0203

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00703

Gnomad FIN

AF:

0.0544

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0307

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.0241

AC:

6038

AN:

250834

Hom.:

105

AF XY:

0.0244

AC XY:

3302

AN XY:

135554

show subpopulations

Gnomad AFR exome

AF:

0.00493

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.0302

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00605

Gnomad FIN exome

AF:

0.0523

Gnomad NFE exome

AF:

0.0319

Gnomad OTH exome

AF:

0.0268

GnomAD4 exome

AF:

0.0284

AC:

41433

AN:

1461420

Hom.:

641

Cov.:

AF XY:

0.0276

AC XY:

20060

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.00415

Gnomad4 AMR exome

AF:

0.0151

Gnomad4 ASJ exome

AF:

0.0294

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00638

Gnomad4 FIN exome

AF:

0.0492

Gnomad4 NFE exome

AF:

0.0315

Gnomad4 OTH exome

AF:

0.0243

GnomAD4 genome

AF:

0.0226

AC:

3441

AN:

152288

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

1755

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00527

Gnomad4 AMR

AF:

0.0202

Gnomad4 ASJ

AF:

0.0268

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.0544

Gnomad4 NFE

AF:

0.0308

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0273

Hom.:

Bravo

AF:

0.0196

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0321

EpiControl

AF:

0.0322

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2015	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 specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr2966Thr in exon 53 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 3.2% (272/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs111995400). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.53

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over