chr5-13721269-A-G

Variant names:

• chr5-13721269-A-G
• rs17203442
• NM_001369.3:c.12034-24T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.12034-24T>C variant causes a intron change. The variant allele was found at a frequency of 0.13 in 1,613,384 control chromosomes in the GnomAD database, including 15,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.11 (1181 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14478 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.20
• Publications: 7 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-13721269-A-G is Benign according to our data. Variant chr5-13721269-A-G is described in ClinVar as Benign. ClinVar VariationId is 257989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.12034-24T>C		intron_variant	Intron 70 of 78	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.12034-24T>C		intron_variant	Intron 70 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.11989-24T>C		intron_variant	Intron 70 of 78			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16404 AN: 152158 Hom.: 1181 Cov.: 33

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.108 AC: 26860 AN: 249706 AF XY: 0.106

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.0672

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.00448

Gnomad FIN exome AF: 0.209

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.133 AC: 194086 AN: 1461108 Hom.: 14478 Cov.: 32 AF XY: 0.130 AC XY: 94712 AN XY: 726912

African (AFR) AF: 0.0282 AC: 945 AN: 33468

American (AMR) AF: 0.0716 AC: 3202 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3747 AN: 26132

East Asian (EAS) AF: 0.00219 AC: 87 AN: 39682

South Asian (SAS) AF: 0.0272 AC: 2346 AN: 86204

European-Finnish (FIN) AF: 0.204 AC: 10887 AN: 53358

Middle Eastern (MID) AF: 0.0914 AC: 527 AN: 5768

European-Non Finnish (NFE) AF: 0.149 AC: 165261 AN: 1111404

Other (OTH) AF: 0.117 AC: 7084 AN: 60376

GnomAD4 genome AF: 0.108 AC: 16399 AN: 152276 Hom.: 1181 Cov.: 33 AF XY: 0.109 AC XY: 8098 AN XY: 74426

African (AFR) AF: 0.0334 AC: 1387 AN: 41576

American (AMR) AF: 0.102 AC: 1557 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 507 AN: 3472

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5188

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4824

European-Finnish (FIN) AF: 0.219 AC: 2322 AN: 10596

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10041 AN: 68006

Other (OTH) AF: 0.113 AC: 240 AN: 2116

Alfa AF: 0.131 Hom.: 6297

Bravo AF: 0.0968

Asia WGS AF: 0.0250 AC: 88 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 3 Benign:1

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.54
PhyloP100		5.2
BranchPoint Hunter		5.0
Mutation Taster		=97/3	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: rs17203442; hg19: chr5-13721378;