5-13886135-CAAAAAAAAAA-CAAAAAAAA

Position:

• chr5-13886135-CAAAAAAAAAA-CAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.2578-8_2578-7delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,297,238 control chromosomes in the GnomAD database, including 6,936 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (5590 hom., cov: 0)
  • Exomes 𝑓: 0.25 (1346 hom.)
• Consequence: DNAH5 NM_001369.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0110

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 -16 ACMG points.

• BP6: Variant 5-13886135-CAA-C is Benign according to our data. Variant chr5-13886135-CAA-C is described in ClinVar as [Likely_benign]. Clinvar id is 402729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13886135-CAA-C is described in Lovd as [Benign]. Variant chr5-13886135-CAA-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.2578-8_2578-7delTT		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.2578-8_2578-7delTT		splice_region_variant, intron_variant		1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.2533-8_2533-7delTT		splice_region_variant, intron_variant				ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.254-10436_254-10435delAA		intron_variant		4
ENSG00000251423	ENST00000637153.1	n.214-10436_214-10435delAA		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.318 AC: 39251 AN: 123580 Hom.: 5593 Cov.: 0

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.320

GnomAD3 exomes AF: 0.206 AC: 12657 AN: 61536 Hom.: 9 AF XY: 0.197 AC XY: 6200 AN XY: 31394

Gnomad AFR exome AF: 0.274

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.224

Gnomad SAS exome AF: 0.218

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.208

GnomAD4 exome AF: 0.249 AC: 292166 AN: 1173680 Hom.: 1346 AF XY: 0.249 AC XY: 144142 AN XY: 579432

Gnomad4 AFR exome AF: 0.287

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.222

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.248

GnomAD4 genome AF: 0.318 AC: 39247 AN: 123558 Hom.: 5590 Cov.: 0 AF XY: 0.316 AC XY: 18508 AN XY: 58572

Gnomad4 AFR AF: 0.372

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.281

Gnomad4 SAS AF: 0.417

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.323

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 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	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 22, 2022	- -

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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2019

- -

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;