5-13886135-CAAAAAAAAAA-CAAAAAAA

Position:

• chr5-13886135-CAAAAAAAAAA-CAAAAAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001369.3(DNAH5):​c.2578-9_2578-7delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,297,624 control chromosomes in the GnomAD database, including 4,081 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.21 (2646 hom., cov: 0)
  • Exomes 𝑓: 0.22 (1435 hom.)
• Consequence: DNAH5 NM_001369.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.52

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]

ENSG00000251423 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 5-13886135-CAAA-C is Benign according to our data. Variant chr5-13886135-CAAA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 351200.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}. Variant chr5-13886135-CAAA-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.2578-9_2578-7delTTT		splice_region_variant, intron_variant		ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.2578-9_2578-7delTTT		splice_region_variant, intron_variant		1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.2533-9_2533-7delTTT		splice_region_variant, intron_variant				ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.254-10437_254-10435delAAA		intron_variant		4
ENSG00000251423	ENST00000637153.1	n.214-10437_214-10435delAAA		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.213 AC: 26373 AN: 123808 Hom.: 2647 Cov.: 0

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.282

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.0629

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.236

Gnomad OTH AF: 0.223

GnomAD3 exomes AF: 0.206 AC: 12664 AN: 61536 Hom.: 19 AF XY: 0.197 AC XY: 6174 AN XY: 31394

Gnomad AFR exome AF: 0.179

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.0888

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.220 AC: 257846 AN: 1173838 Hom.: 1435 AF XY: 0.219 AC XY: 126977 AN XY: 579636

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.229

Gnomad4 EAS exome AF: 0.0664

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.217

GnomAD4 genome AF: 0.213 AC: 26357 AN: 123786 Hom.: 2646 Cov.: 0 AF XY: 0.214 AC XY: 12587 AN XY: 58684

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.282

Gnomad4 ASJ AF: 0.282

Gnomad4 EAS AF: 0.0620

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.236

Gnomad4 OTH AF: 0.221

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 03, 2015	This alteration is classified as likely 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 24, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

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: rs71600031; hg19: chr5-13886244;