dbSNP rs146191243: DNAH5:p.Lys1329Lys (chr5-13867840-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001369.3(DNAH5):c.3987A>G(p.Lys1329Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,002 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0099 ( 12 hom., cov: 32)

Exomes 𝑓: 0.015 ( 204 hom. )

Consequence

DNAH5
NM_001369.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.325

Publications

4 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:

DNAH5-AS1 (HGNC:40187):

DNAH5-AS1 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=-0.54).

BP6

Variant 5-13867840-T-C is Benign according to our data. Variant chr5-13867840-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.325 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00989 (1505/152226) while in subpopulation NFE AF = 0.0154 (1048/68006). AF 95% confidence interval is 0.0146. There are 12 homozygotes in GnomAd4. There are 715 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

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.3987A>G	p.Lys1329Lys	synonymous	Exon 25 of 79	NP_001360.1	Q8TE73
	DNAH5-AS1	NR_199035.1		n.117+7285T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.3987A>G	p.Lys1329Lys	synonymous	Exon 25 of 79	ENSP00000265104.4	Q8TE73
DNAH5	ENST00000681290.1		c.3942A>G	p.Lys1314Lys	synonymous	Exon 25 of 79	ENSP00000505288.1	A0A7P0Z455
DNAH5-AS1	ENST00000503244.2	TSL:4	n.253+7285T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00989

AC:

1505

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00695

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00353

Gnomad FIN

AF:

0.0142

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0109

AC:

2728

AN:

251142

AF XY:

0.0112

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00541

Gnomad ASJ exome

AF:

0.0158

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0157

Gnomad NFE exome

AF:

0.0161

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.0147

AC:

21499

AN:

1461776

Hom.:

204

Cov.:

AF XY:

0.0144

AC XY:

10499

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00206

AC:

AN:

33476

American (AMR)

AF:

0.00579

AC:

259

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0140

AC:

367

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00326

AC:

281

AN:

86254

European-Finnish (FIN)

AF:

0.0139

AC:

741

AN:

53420

Middle Eastern (MID)

AF:

0.0187

AC:

108

AN:

5760

European-Non Finnish (NFE)

AF:

0.0170

AC:

18910

AN:

1111924

Other (OTH)

AF:

0.0126

AC:

763

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1153

2305

3458

4610

5763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

712

1424

2136

2848

3560

<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:

0.00989

AC:

1505

AN:

152226

Hom.:

Cov.:

AF XY:

0.00961

AC XY:

715

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00262

AC:

109

AN:

41552

American (AMR)

AF:

0.00688

AC:

105

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00374

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0142

AC:

151

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0154

AC:

1048

AN:

68006

Other (OTH)

AF:

0.0128

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

155

233

310

388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0122

Hom.:

Bravo

AF:

0.00999

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0171

EpiControl

AF:

0.0187

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (3)

not provided (2)

not specified (2)

Primary ciliary dyskinesia 3 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.4

(source)

DANN

Benign

0.68

PhyloP100

0.33

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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