5-13886135-CAAAAAAAAAA-CAAAAAAAA

Variant names:

• chr5-13886135-CAA-C
• rs71600031
• NM_001369.3:c.2578-8_2578-7delTT

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251423 (HGNC:40187):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 402729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.2578-8_2578-7delTT		splice_region_variant, intron_variant	Intron 17 of 78	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.2578-8_2578-7delTT		splice_region_variant, intron_variant	Intron 17 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.2533-8_2533-7delTT		splice_region_variant, intron_variant	Intron 17 of 78			ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.254-10453_254-10452delAA		intron_variant	Intron 1 of 2	4
ENSG00000251423	ENST00000637153.1	n.214-10453_214-10452delAA		intron_variant	Intron 1 of 2	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

GnomAD2 exomes AF: 0.206 AC: 12657 AN: 61536 AF XY: 0.197

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.287 AC: 7362 AN: 25682

American (AMR) AF: 0.202 AC: 5261 AN: 26078

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 4262 AN: 19880

East Asian (EAS) AF: 0.218 AC: 6688 AN: 30652

South Asian (SAS) AF: 0.277 AC: 17255 AN: 62186

European-Finnish (FIN) AF: 0.222 AC: 6655 AN: 30002

Middle Eastern (MID) AF: 0.234 AC: 795 AN: 3402

European-Non Finnish (NFE) AF: 0.250 AC: 231744 AN: 926800

Other (OTH) AF: 0.248 AC: 12144 AN: 48998

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.372 AC: 12541 AN: 33702

American (AMR) AF: 0.286 AC: 3436 AN: 12018

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 827 AN: 3004

East Asian (EAS) AF: 0.281 AC: 1006 AN: 3576

South Asian (SAS) AF: 0.417 AC: 1598 AN: 3832

European-Finnish (FIN) AF: 0.245 AC: 1466 AN: 5980

Middle Eastern (MID) AF: 0.297 AC: 69 AN: 232

European-Non Finnish (NFE) AF: 0.298 AC: 17523 AN: 58750

Other (OTH) AF: 0.323 AC: 535 AN: 1654

Alfa AF: 0.0776 Hom.: 15

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Jul 30, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs71600031; hg19: chr5-13886244; COSMIC: COSV54239311;