5-13841918-CAAAAAAAAAAA-CAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001369.3(DNAH5):​c.5272-16_5272-15dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.015 (52 hom., cov: 0)
  • Exomes 𝑓: 0.019 (4 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.5272-16_5272-15dupTT		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_5272-14insTT		intron_variant	Intron 32 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.5227-15_5227-14insTT		intron_variant	Intron 32 of 78			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 1561 AN: 104512 Hom.: 52 Cov.: 0

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00852

Gnomad ASJ AF: 0.0155

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00925

Gnomad OTH AF: 0.0122

GnomAD4 exome AF: 0.0188 AC: 9070 AN: 483186 Hom.: 4 Cov.: 0 AF XY: 0.0190 AC XY: 4974 AN XY: 261124

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

African (AFR) AF: 0.0146 AC: 181 AN: 12424

American (AMR) AF: 0.0180 AC: 342 AN: 19022

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 220 AN: 13720

East Asian (EAS) AF: 0.0438 AC: 1154 AN: 26324

South Asian (SAS) AF: 0.0336 AC: 1500 AN: 44638

European-Finnish (FIN) AF: 0.0219 AC: 579 AN: 26480

Middle Eastern (MID) AF: 0.0218 AC: 43 AN: 1976

European-Non Finnish (NFE) AF: 0.0147 AC: 4608 AN: 313480

Other (OTH) AF: 0.0176 AC: 443 AN: 25122

⚠️ 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: 0.0149 AC: 1560 AN: 104506 Hom.: 52 Cov.: 0 AF XY: 0.0163 AC XY: 768 AN XY: 47190

African (AFR) AF: 0.0121 AC: 341 AN: 28146

American (AMR) AF: 0.00852 AC: 74 AN: 8688

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 46 AN: 2960

East Asian (EAS) AF: 0.140 AC: 434 AN: 3100

South Asian (SAS) AF: 0.0215 AC: 58 AN: 2692

European-Finnish (FIN) AF: 0.0291 AC: 55 AN: 1888

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

European-Non Finnish (NFE) AF: 0.00925 AC: 506 AN: 54722

Other (OTH) AF: 0.0122 AC: 17 AN: 1392

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 3 Uncertain:1

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35337694; hg19: chr5-13842027;