rs6554812

Positions:

• chr5-13762863-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001369.3(DNAH5):​c.10140A>G​(p.Glu3380=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,612,358 control chromosomes in the GnomAD database, including 68,300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7746 hom., cov: 33)
  • Exomes 𝑓: 0.28 (60554 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0450

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 5-13762863-T-C is Benign according to our data. Variant chr5-13762863-T-C is described in ClinVar as [Benign]. Clinvar id is 163137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13762863-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.045 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.10140A>G	p.Glu3380=	synonymous_variant	60/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.10140A>G	p.Glu3380=	synonymous_variant	60/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1	c.10095A>G	p.Glu3365=	synonymous_variant	60/79			ENSP00000505288	A1
DNAH5	ENST00000504001.3	n.648A>G		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46838 AN: 152010 Hom.: 7726 Cov.: 33

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.280

GnomAD3 exomes AF: 0.298 AC: 74871 AN: 250966 Hom.: 12319 AF XY: 0.302 AC XY: 40987 AN XY: 135644

Gnomad AFR exome AF: 0.367

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.0947

Gnomad SAS exome AF: 0.442

Gnomad FIN exome AF: 0.424

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.280 AC: 408259 AN: 1460230 Hom.: 60554 Cov.: 35 AF XY: 0.284 AC XY: 206515 AN XY: 726510

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.294

Gnomad4 ASJ exome AF: 0.208

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.434

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome AF: 0.308 AC: 46909 AN: 152128 Hom.: 7746 Cov.: 33 AF XY: 0.315 AC XY: 23440 AN XY: 74368

Gnomad4 AFR AF: 0.368

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.113

Gnomad4 SAS AF: 0.441

Gnomad4 FIN AF: 0.442

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.286

Alfa AF: 0.268 Hom.: 11384

Bravo AF: 0.291

Asia WGS AF: 0.329 AC: 1144 AN: 3478

EpiCase AF: 0.257

EpiControl AF: 0.257

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Primary ciliary dyskinesia 3 Benign:3

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu3380Glu in exon 60 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 36.3% (1601/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs6554812). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.2
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs6554812; hg19: chr5-13762972; COSMIC: COSV54228724;