5-13867994-TAA-TAAA

Variant names:

• chr5-13867994-T-TA
• rs35398031
• NM_001369.3:c.3835-3dupT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001369.3(DNAH5):​c.3835-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: DNAH5 NM_001369.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.454
• Publications: 8 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 5-13867994-T-TA is Benign according to our data. Variant chr5-13867994-T-TA is described in ClinVar as Likely_benign. ClinVar VariationId is 454771.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.3835-3dupT		splice_region_variant, intron_variant	Intron 24 of 78	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.3835-3_3835-2insT		splice_region_variant, intron_variant	Intron 24 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.3790-3_3790-2insT		splice_region_variant, intron_variant	Intron 24 of 78			ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.253+7439_253+7440insA		intron_variant	Intron 1 of 2	4
ENSG00000251423	ENST00000637153.1	n.213+7479_213+7480insA		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.000423 AC: 64 AN: 151464 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000192 AC: 46 AN: 239752 AF XY: 0.000131

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.000216

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000224 AC: 325 AN: 1447808 Hom.: 0 Cov.: 0 AF XY: 0.000190 AC XY: 137 AN XY: 720446

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

African (AFR) AF: 0.00124 AC: 41 AN: 33076

American (AMR) AF: 0.000204 AC: 9 AN: 44190

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25910

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39278

South Asian (SAS) AF: 0.000140 AC: 12 AN: 85704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.000219 AC: 241 AN: 1101184

Other (OTH) AF: 0.000234 AC: 14 AN: 59770

⚠️ 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: 0.000429 AC: 65 AN: 151580 Hom.: 0 Cov.: 0 AF XY: 0.000405 AC XY: 30 AN XY: 74036

African (AFR) AF: 0.00128 AC: 53 AN: 41272

American (AMR) AF: 0.000197 AC: 3 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67880

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.00 Hom.: 1450

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DNAH5-related disorder Benign:1

Jan 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=93/7	polymorphism

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: rs35398031; hg19: chr5-13868103; COSMIC: COSV54244472;