Genetic Variant DNAH5:p.Thr3491Thr (chr5-13754285-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. T3491T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.35 ( 9572 hom., cov: 32)

Exomes 𝑓: 0.36 ( 95037 hom. )

Consequence

DNAH5
NM_001369.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.38

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 163136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.10473G>A	p.Thr3491Thr	synonymous	Exon 62 of 79	NP_001360.1	Q8TE73

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.10473G>A	p.Thr3491Thr	synonymous	Exon 62 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.10428G>A	p.Thr3476Thr	synonymous	Exon 62 of 79	ENSP00000505288.1	A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.349

AC:

53051

AN:

151864

Hom.:

9571

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.347

AC:

87171

AN:

251064

AF XY:

0.356

show subpopulations

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 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.:

AF XY:

0.361

AC XY:

262358

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.337

AC:

11292

AN:

33474

American (AMR)

AF:

0.310

AC:

13858

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.338

AC:

8841

AN:

26132

East Asian (EAS)

AF:

0.134

AC:

5301

AN:

39694

South Asian (SAS)

AF:

0.453

AC:

39079

AN:

86254

European-Finnish (FIN)

AF:

0.379

AC:

20265

AN:

53418

Middle Eastern (MID)

AF:

0.356

AC:

2052

AN:

5766

European-Non Finnish (NFE)

AF:

0.360

AC:

399945

AN:

1111796

Other (OTH)

AF:

0.355

AC:

21422

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

18917

37834

56752

75669

94586

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12694

25388

38082

50776

63470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.349

AC:

53074

AN:

151984

Hom.:

9572

Cov.:

AF XY:

0.352

AC XY:

26140

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.339

AC:

14052

AN:

41438

American (AMR)

AF:

0.320

AC:

4887

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

1161

AN:

3466

East Asian (EAS)

AF:

0.133

AC:

688

AN:

5168

South Asian (SAS)

AF:

0.461

AC:

2217

AN:

4808

European-Finnish (FIN)

AF:

0.399

AC:

4212

AN:

10548

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.362

AC:

24616

AN:

67976

Other (OTH)

AF:

0.356

AC:

749

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1792

3584

5375

7167

8959

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

538

1076

1614

2152

2690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.344

Hom.:

6626

Bravo

AF:

0.337

Asia WGS

AF:

0.345

AC:

1197

AN:

3478

EpiCase

AF:

0.361

EpiControl

AF:

0.359

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (3)

Primary ciliary dyskinesia 3 (3)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.066

(source)

DANN

Benign

0.48

PhyloP100

-2.4

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over