chr5-13788926-A-G

Position:

chr5-13788926-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001369.3(DNAH5):c.8449-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,612,092 control chromosomes in the GnomAD database, including 838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 65 hom., cov: 33)

Exomes 𝑓: 0.031 ( 773 hom. )

Consequence

DNAH5
NM_001369.3 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0003573

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.566

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 5-13788926-A-G is Benign according to our data. Variant chr5-13788926-A-G is described in ClinVar as [Benign]. Clinvar id is 178746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13788926-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0248 (3775/152332) while in subpopulation NFE AF= 0.0338 (2299/68024). AF 95% confidence interval is 0.0326. There are 65 homozygotes in gnomad4. There are 1908 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 65 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.8449-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.8449-12T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001369.3	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.8404-12T>C		splice_polypyrimidine_tract_variant, intron_variant				A1

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3775

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00586

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0221

Gnomad ASJ

AF:

0.0274

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0105

Gnomad FIN

AF:

0.0586

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0338

Gnomad OTH

AF:

0.0239

GnomAD3 exomes

AF:

0.0267

AC:

6691

AN:

250842

Hom.:

121

AF XY:

0.0272

AC XY:

3689

AN XY:

135614

show subpopulations

Gnomad AFR exome

AF:

0.00530

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.0320

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00977

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0355

Gnomad OTH exome

AF:

0.0300

GnomAD4 exome

AF:

0.0308

AC:

45018

AN:

1459760

Hom.:

773

Cov.:

AF XY:

0.0301

AC XY:

21860

AN XY:

726344

show subpopulations

Gnomad4 AFR exome

AF:

0.00520

Gnomad4 AMR exome

AF:

0.0155

Gnomad4 ASJ exome

AF:

0.0320

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0101

Gnomad4 FIN exome

AF:

0.0542

Gnomad4 NFE exome

AF:

0.0340

Gnomad4 OTH exome

AF:

0.0276

GnomAD4 genome

AF:

0.0248

AC:

3775

AN:

152332

Hom.:

Cov.:

AF XY:

0.0256

AC XY:

1908

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00584

Gnomad4 AMR

AF:

0.0220

Gnomad4 ASJ

AF:

0.0274

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.0586

Gnomad4 NFE

AF:

0.0338

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0277

Hom.:

Bravo

AF:

0.0213

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	8449-12T>C in intron 50 of DNAH5: This variant is not expected to have clinical significance because it has been identified in 3.3% (283/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs111313933). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

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

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.0

DANN

Benign

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00036

dbscSNV1_RF

Benign

0.080

SpliceAI score (max)

0.030

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