rs137878131

chr5-13902068-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_001369.3(DNAH5):c.1715T>G(p.Leu572Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000637 in 1,604,074 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L572L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (2 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 6.93

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 5-13902068-A-C is Benign according to our data. Variant chr5-13902068-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 351208.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000625 (908/1451726) while in subpopulation MID AF= 0.0098 (56/5712). AF 95% confidence interval is 0.00775. There are 2 homozygotes in gnomad4_exome. There are 486 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.1715T>G	p.Leu572Trp	missense_variant	13/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.1715T>G	p.Leu572Trp	missense_variant	13/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.1670T>G	p.Leu557Trp	missense_variant	13/79			A1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000814 AC: 196 AN: 240660 Hom.: 0 AF XY: 0.000931 AC XY: 121 AN XY: 129960

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.000649

Gnomad ASJ exome AF: 0.000935

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000305

Gnomad FIN exome AF: 0.000337

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00169

GnomAD4 exome AF: 0.000625 AC: 908 AN: 1451726 Hom.: 2 Cov.: 29 AF XY: 0.000673 AC XY: 486 AN XY: 721788

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000520

Gnomad4 ASJ exome AF: 0.00124

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000329

Gnomad4 FIN exome AF: 0.000211

Gnomad4 NFE exome AF: 0.000618

Gnomad4 OTH exome AF: 0.00112

GnomAD4 genome AF: 0.000748 AC: 114 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74500

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.000842

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000709 AC: 86

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 3 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 09, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Sep 12, 2023	The DNAH5 c.1715T>G (p.Leu572Trp) variant has been reported in one individual with Kartagener’s syndrome, but was not determined to be causative (Ozkavukcu S et al., PMID: 29402277). Additionally, DNAH5 c.1715T>G was published in an individual with situs inversus, but the protein change reported is p.Leu573*, so it is unclear if this is the same variant or a report of a distinct variant (Nöthe-Menchen T et al., PMID: 31638833). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.1% in the European (non-Finnish) population, which is consistent with carrier status of primary ciliary dyskinesia. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to DNAH5 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Primary ciliary dyskinesia Uncertain:2 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 16, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Oct 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 2022	This alteration is classified as likely 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	Invitae	Jan 29, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 22, 2018

The p.Leu572Trp variant in DNAH5 has not been previously reported in individuals with primary ciliary dyskinesia, but has been identified in 0.1% (147/120780) o f European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs13787813). Computational prediction tools and conse rvation analysis suggest that the p.Leu572Trp variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Leu572Trp variant is uncertain. ACMG/A MP Criteria applied: PP3. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 12, 2023

Identified in a patient with primary ciliary dyskinesia in published literature, however additional genotype and phenotype information was not provided (Nothe-Menchen et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 35737725, 29402277, 31638833) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Polyphen		0.82	P
Vest4		0.81
MVP		0.90
MPC		0.61
ClinPred		0.13	T
GERP RS		4.9
Varity_R		0.91
gMVP		0.84

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: rs137878131; hg19: chr5-13902177; COSMIC: COSV99035471; COSMIC: COSV99035471;