rs148099176

Variant names:

• chr5-13793500-C-T
• rs148099176
• NM_001369.3:c.8224+15G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001369.3(DNAH5):​c.8224+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000904 in 1,605,386 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (5 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0750

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-13793500-C-T is Benign according to our data. Variant chr5-13793500-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258062.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000926 (1345/1453152) while in subpopulation MID AF= 0.00573 (33/5756). AF 95% confidence interval is 0.0042. There are 5 homozygotes in gnomad4_exome. There are 668 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.8224+15G>A		intron_variant	Intron 49 of 78	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.8224+15G>A		intron_variant	Intron 49 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.8179+15G>A		intron_variant	Intron 49 of 78			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00750

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000936 AC: 235 AN: 251172 Hom.: 1 AF XY: 0.00104 AC XY: 141 AN XY: 135748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00616

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000925

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000926 AC: 1345 AN: 1453152 Hom.: 5 Cov.: 30 AF XY: 0.000923 AC XY: 668 AN XY: 723506

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00659

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000843

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74448

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00750

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00192 Hom.: 0

Bravo AF: 0.000801

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.8224+15G>A in intron 49 of DNAH5: This variant is not expected to have clinica l significance because it is not located within the conserved splice consensus s equence. It has been identified in 0.1% (79/66666) of European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs14 8099176). -

Primary ciliary dyskinesia 3 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Primary ciliary dyskinesia Benign:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.29

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: rs148099176; hg19: chr5-13793609;