5-13841918-CAAAAAAAAAAA-CAAAAAAAAAAAA

Variant names:

• chr5-13841918-C-CA
• rs35337694
• NM_001369.3:c.5272-15dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_001369.3(DNAH5):​c.5272-15dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.49 (12437 hom., cov: 0)
  • Exomes 𝑓: 0.15 (97 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.617
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 5-13841918-C-CA is Benign according to our data. Variant chr5-13841918-C-CA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 351094.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.5272-15dupT		intron_variant	Intron 32 of 78	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.5272-15_5272-14insT		intron_variant	Intron 32 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.5227-15_5227-14insT		intron_variant	Intron 32 of 78			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.487 AC: 50848 AN: 104496 Hom.: 12441 Cov.: 0

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.526

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.505

GnomAD4 exome AF: 0.147 AC: 69437 AN: 473344 Hom.: 97 Cov.: 0 AF XY: 0.148 AC XY: 37774 AN XY: 255706

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

African (AFR) AF: 0.0990 AC: 1200 AN: 12124

American (AMR) AF: 0.126 AC: 2351 AN: 18652

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 1734 AN: 13430

East Asian (EAS) AF: 0.0886 AC: 2306 AN: 26038

South Asian (SAS) AF: 0.166 AC: 7328 AN: 44040

European-Finnish (FIN) AF: 0.169 AC: 4378 AN: 25872

Middle Eastern (MID) AF: 0.150 AC: 287 AN: 1918

European-Non Finnish (NFE) AF: 0.151 AC: 46314 AN: 306726

Other (OTH) AF: 0.144 AC: 3539 AN: 24544

⚠️ 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: 0.486 AC: 50832 AN: 104490 Hom.: 12437 Cov.: 0 AF XY: 0.479 AC XY: 22584 AN XY: 47158

African (AFR) AF: 0.355 AC: 9976 AN: 28100

American (AMR) AF: 0.515 AC: 4465 AN: 8662

Ashkenazi Jewish (ASJ) AF: 0.524 AC: 1553 AN: 2962

East Asian (EAS) AF: 0.212 AC: 657 AN: 3106

South Asian (SAS) AF: 0.555 AC: 1489 AN: 2684

European-Finnish (FIN) AF: 0.479 AC: 884 AN: 1844

Middle Eastern (MID) AF: 0.520 AC: 78 AN: 150

European-Non Finnish (NFE) AF: 0.559 AC: 30674 AN: 54832

Other (OTH) AF: 0.504 AC: 700 AN: 1388

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 03, 2014

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. -

not provided Benign:1

Aug 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35337694; hg19: chr5-13842027;