rs146191243

chr5-13867840-T-Cchr5-13867840-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001369.3(DNAH5):c.3987A>G(p.Lys1329=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,002 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (12 hom., cov: 32)
  • Exomes 𝑓: 0.015 (204 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.325

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 5-13867840-T-C is Benign according to our data. Variant chr5-13867840-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 163151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13867840-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.325 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00989 (1505/152226) while in subpopulation NFE AF= 0.0154 (1048/68006). AF 95% confidence interval is 0.0146. There are 12 homozygotes in gnomad4. There are 715 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.3987A>G	p.Lys1329=	synonymous_variant	25/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.3987A>G	p.Lys1329=	synonymous_variant	25/79	1	NM_001369.3	P4
	ENST00000503244.2	n.253+7285T>C		intron_variant, non_coding_transcript_variant		4
DNAH5	ENST00000681290.1	c.3942A>G	p.Lys1314=	synonymous_variant	25/79			A1
	ENST00000637153.1	n.213+7325T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 1505 AN: 152108 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00695

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0109 AC: 2728 AN: 251142 Hom.: 26 AF XY: 0.0112 AC XY: 1525 AN XY: 135716

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00541

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00300

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0147 AC: 21499 AN: 1461776 Hom.: 204 Cov.: 33 AF XY: 0.0144 AC XY: 10499 AN XY: 727200

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00579

Gnomad4 ASJ exome AF: 0.0140

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00326

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.00989 AC: 1505 AN: 152226 Hom.: 12 Cov.: 32 AF XY: 0.00961 AC XY: 715 AN XY: 74436

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.00688

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0122 Hom.: 8

Bravo AF: 0.00999

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0171

EpiControl AF: 0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2015	This alteration is classified as 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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Lys1329Lys in exon 25 of DNAH5: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 1.8% (158/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs146191243). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	7.4
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs146191243; hg19: chr5-13867949;