NM_001369.3:c.5272-15delT

Variant names:

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

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.5272-15delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (3668 hom., cov: 0)
  • Exomes 𝑓: 0.24 (381 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -16 ACMG points.

• BP6: Variant 5-13841918-CA-C is Benign according to our data. Variant chr5-13841918-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 351096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.5272-15delT		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.5272-15delT		intron_variant	Intron 32 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.5227-15delT		intron_variant	Intron 32 of 78			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 32804 AN: 104540 Hom.: 3671 Cov.: 0

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.334

GnomAD4 exome AF: 0.237 AC: 112952 AN: 475680 Hom.: 381 Cov.: 0 AF XY: 0.233 AC XY: 59978 AN XY: 256968

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

African (AFR) AF: 0.186 AC: 2275 AN: 12222

American (AMR) AF: 0.198 AC: 3686 AN: 18652

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 2948 AN: 13442

East Asian (EAS) AF: 0.290 AC: 7731 AN: 26634

South Asian (SAS) AF: 0.175 AC: 7604 AN: 43460

European-Finnish (FIN) AF: 0.229 AC: 6006 AN: 26218

Middle Eastern (MID) AF: 0.215 AC: 416 AN: 1934

European-Non Finnish (NFE) AF: 0.248 AC: 76322 AN: 308318

Other (OTH) AF: 0.240 AC: 5964 AN: 24800

⚠️ 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: 0.314 AC: 32792 AN: 104534 Hom.: 3668 Cov.: 0 AF XY: 0.317 AC XY: 14955 AN XY: 47224

African (AFR) AF: 0.255 AC: 7159 AN: 28092

American (AMR) AF: 0.344 AC: 2993 AN: 8702

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 926 AN: 2962

East Asian (EAS) AF: 0.549 AC: 1714 AN: 3122

South Asian (SAS) AF: 0.347 AC: 933 AN: 2690

European-Finnish (FIN) AF: 0.394 AC: 747 AN: 1896

Middle Eastern (MID) AF: 0.273 AC: 42 AN: 154

European-Non Finnish (NFE) AF: 0.320 AC: 17529 AN: 54760

Other (OTH) AF: 0.334 AC: 465 AN: 1392

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 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. -

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 -

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; COSMIC: COSV54203833;