rs115004914

chr5-13900212-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001369.3(DNAH5):c.2253C>A(p.Asn751Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,612,604 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (130 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.655

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028903186).
• BP6: Variant 5-13900212-G-T is Benign according to our data. Variant chr5-13900212-G-T is described in ClinVar as [Benign]. Clinvar id is 178754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13900212-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00517 (787/152296) while in subpopulation SAS AF= 0.0332 (160/4824). AF 95% confidence interval is 0.029. There are 2 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.2253C>A	p.Asn751Lys	missense_variant	15/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.2253C>A	p.Asn751Lys	missense_variant	15/79	1	NM_001369.3	P4
	ENST00000503244.2	n.3088G>T		non_coding_transcript_exon_variant	3/3	4
DNAH5	ENST00000681290.1	c.2208C>A	p.Asn736Lys	missense_variant	15/79			A1
	ENST00000637153.1	n.3048G>T		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.00520 AC: 792 AN: 152178 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00972 AC: 2439 AN: 250898 Hom.: 42 AF XY: 0.0113 AC XY: 1534 AN XY: 135646

Gnomad AFR exome AF: 0.000557

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00212

Gnomad SAS exome AF: 0.0387

Gnomad FIN exome AF: 0.00300

Gnomad NFE exome AF: 0.00650

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.00728 AC: 10631 AN: 1460308 Hom.: 130 Cov.: 28 AF XY: 0.00847 AC XY: 6155 AN XY: 726610

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00541

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.0391

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.00505

Gnomad4 OTH exome AF: 0.00923

GnomAD4 genome AF: 0.00517 AC: 787 AN: 152296 Hom.: 2 Cov.: 32 AF XY: 0.00575 AC XY: 428 AN XY: 74476

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.0332

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00557

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00645 Hom.: 9

Bravo AF: 0.00465

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.0101 AC: 1232

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00711

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2020	This variant is associated with the following publications: (PMID: 31213628) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DNAH5: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 03, 2016	p.Asn751Lys in exon 15 of DNAH5: This variant is not expected to have clinical s ignificance because it has been identified in 3.8% (635/16496) of South Asian ch romosomes, including 18 homozygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs115004914). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2014	- -

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 09, 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. -

Primary ciliary dyskinesia 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	17
Dann	Benign	0.73
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.085	N
MutationTaster	Benign	0.85	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.084
Sift	Benign	0.98	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.58		Gain of disorder (P = 0.06);
MPC		0.34
ClinPred		0.011	T
GERP RS		1.3
Varity_R		0.056
gMVP		0.21

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: rs115004914; hg19: chr5-13900321;