rs368185722

Variant names:

• chr5-13841936-A-G
• rs368185722
• NM_001369.3:c.5272-32T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001369.3(DNAH5):​c.5272-32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,071,394 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 30)
  • Exomes 𝑓: 0.024 (283 hom.)
• Consequence: DNAH5 NM_001369.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0610
• Publications: 1 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: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-13841936-A-G is Benign according to our data. Variant chr5-13841936-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 258043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.012 (1790/149568) while in subpopulation NFE AF = 0.0203 (1368/67404). AF 95% confidence interval is 0.0194. There are 26 homozygotes in GnomAd4. There are 830 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AD,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1792 AN: 149462 Hom.: 26 Cov.: 30

Gnomad AFR AF: 0.00402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00613

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00375

Gnomad FIN AF: 0.00595

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.00538

GnomAD2 exomes AF: 0.0203 AC: 4047 AN: 199594 AF XY: 0.0204

Gnomad AFR exome AF: 0.00821

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0461

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00918

Gnomad NFE exome AF: 0.0309

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0236 AC: 21799 AN: 921826 Hom.: 283 Cov.: 13 AF XY: 0.0236 AC XY: 11301 AN XY: 478488

African (AFR) AF: 0.00776 AC: 161 AN: 20758

American (AMR) AF: 0.0151 AC: 526 AN: 34944

Ashkenazi Jewish (ASJ) AF: 0.0470 AC: 988 AN: 21014

East Asian (EAS) AF: 0.0000840 AC: 3 AN: 35720

South Asian (SAS) AF: 0.00851 AC: 581 AN: 68306

European-Finnish (FIN) AF: 0.0138 AC: 630 AN: 45668

Middle Eastern (MID) AF: 0.0376 AC: 148 AN: 3938

European-Non Finnish (NFE) AF: 0.0273 AC: 17731 AN: 649558

Other (OTH) AF: 0.0246 AC: 1031 AN: 41920

GnomAD4 genome AF: 0.0120 AC: 1790 AN: 149568 Hom.: 26 Cov.: 30 AF XY: 0.0114 AC XY: 830 AN XY: 73082

African (AFR) AF: 0.00401 AC: 162 AN: 40388

American (AMR) AF: 0.0100 AC: 151 AN: 15050

Ashkenazi Jewish (ASJ) AF: 0.00613 AC: 21 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00355 AC: 17 AN: 4790

European-Finnish (FIN) AF: 0.00595 AC: 60 AN: 10088

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

European-Non Finnish (NFE) AF: 0.0203 AC: 1368 AN: 67404

Other (OTH) AF: 0.00532 AC: 11 AN: 2068

Alfa AF: 0.0211 Hom.: 11

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 17, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH5-related disorder Benign:1

Aug 07, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.60
PhyloP100		0.061
Mutation Taster		=100/0	polymorphism (auto)

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: rs368185722; hg19: chr5-13842045; COSMIC: COSV54206478;