chr5-13841918-CAA-C

Variant names:

• chr5-13841918-CAA-C
• rs35337694
• NM_001369.3:c.5272-16_5272-15delTT

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.5272-16_5272-15delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 566,636 control chromosomes in the GnomAD database, including 427 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (411 hom., cov: 0)
  • Exomes 𝑓: 0.13 (16 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts 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 -16 ACMG points.

• BP6: Variant 5-13841918-CAA-C is Benign according to our data. Variant chr5-13841918-CAA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.5272-16_5272-15delTT		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.5272-16_5272-15delTT		intron_variant	Intron 32 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.5227-16_5227-15delTT		intron_variant	Intron 32 of 78			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 5686 AN: 104630 Hom.: 410 Cov.: 0

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.00337

Gnomad EAS AF: 0.00191

Gnomad SAS AF: 0.000741

Gnomad FIN AF: 0.00370

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.0375

GnomAD4 exome AF: 0.133 AC: 61598 AN: 462012 Hom.: 16 AF XY: 0.131 AC XY: 32565 AN XY: 248950

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

African (AFR) AF: 0.216 AC: 2603 AN: 12028

American (AMR) AF: 0.124 AC: 2232 AN: 17986

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 1603 AN: 13034

East Asian (EAS) AF: 0.177 AC: 4562 AN: 25778

South Asian (SAS) AF: 0.0955 AC: 4014 AN: 42048

European-Finnish (FIN) AF: 0.132 AC: 3364 AN: 25514

Middle Eastern (MID) AF: 0.124 AC: 231 AN: 1866

European-Non Finnish (NFE) AF: 0.132 AC: 39587 AN: 299702

Other (OTH) AF: 0.141 AC: 3402 AN: 24056

⚠️ 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: 0.0544 AC: 5695 AN: 104624 Hom.: 411 Cov.: 0 AF XY: 0.0553 AC XY: 2614 AN XY: 47234

African (AFR) AF: 0.188 AC: 5289 AN: 28164

American (AMR) AF: 0.0255 AC: 222 AN: 8696

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 10 AN: 2966

East Asian (EAS) AF: 0.00192 AC: 6 AN: 3120

South Asian (SAS) AF: 0.000742 AC: 2 AN: 2694

European-Finnish (FIN) AF: 0.00370 AC: 7 AN: 1894

Middle Eastern (MID) AF: 0.0195 AC: 3 AN: 154

European-Non Finnish (NFE) AF: 0.00190 AC: 104 AN: 54780

Other (OTH) AF: 0.0374 AC: 52 AN: 1390

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 -

Primary ciliary dyskinesia Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

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

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;