5-13901532-A-C

Position:

• chr5-13901532-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.1772T>G​(p.Leu591Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,613,562 control chromosomes in the GnomAD database, including 350 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L591V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.027 (187 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (163 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.462

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001860857).
• BP6: Variant 5-13901532-A-C is Benign according to our data. Variant chr5-13901532-A-C is described in ClinVar as [Benign]. Clinvar id is 226596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13901532-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0891 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.1772T>G	p.Leu591Arg	missense_variant	14/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.1772T>G	p.Leu591Arg	missense_variant	14/79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.1727T>G	p.Leu576Arg	missense_variant	14/79			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4047 AN: 152166 Hom.: 186 Cov.: 33

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00760 AC: 1868 AN: 245676 Hom.: 78 AF XY: 0.00586 AC XY: 781 AN XY: 133220

Gnomad AFR exome AF: 0.0934

Gnomad AMR exome AF: 0.00578

Gnomad ASJ exome AF: 0.00849

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.00400

GnomAD4 exome AF: 0.00316 AC: 4622 AN: 1461278 Hom.: 163 Cov.: 31 AF XY: 0.00278 AC XY: 2023 AN XY: 726882

Gnomad4 AFR exome AF: 0.0977

Gnomad4 AMR exome AF: 0.00617

Gnomad4 ASJ exome AF: 0.00723

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000342

Gnomad4 OTH exome AF: 0.00714

GnomAD4 genome AF: 0.0267 AC: 4060 AN: 152284 Hom.: 187 Cov.: 33 AF XY: 0.0261 AC XY: 1945 AN XY: 74470

Gnomad4 AFR AF: 0.0915

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00580 Hom.: 43

Bravo AF: 0.0299

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0949 AC: 418

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00889 AC: 1077

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00119

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu591Arg in exon 14 of DNAH5: This variant is not expected to have clinical sig nificance because it has been identified in 9.5% (418/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs35090077). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	- -

Primary ciliary dyskinesia 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 16, 2016	- -
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	0.054
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.080	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.049
Sift	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.26
MVP		0.40
MPC		0.15
ClinPred		0.00047	T
GERP RS		2.0
Varity_R		0.079
gMVP		0.22

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: rs35090077; hg19: chr5-13901641;