5-13902053-C-G

Position:

chr5-13902053-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001369.3(DNAH5):c.1730G>C(p.Arg577Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,587,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 3.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 5-13902053-C-G is Pathogenic according to our data. Variant chr5-13902053-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.1730G>C	p.Arg577Thr	missense_variant, splice_region_variant	13/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.1730G>C	p.Arg577Thr	missense_variant, splice_region_variant	13/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.1685G>C	p.Arg562Thr	missense_variant, splice_region_variant	13/79			ENSP00000505288	A1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000216

AC:

AN:

231028

Hom.:

AF XY:

0.00

AC XY:

AN XY:

124632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000493

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1435214

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

713648

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000476

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 3

Pathogenic:3Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	Variant summary: DNAH5 c.1730G>C (p.Arg577Thr) results in a non-conservative amino acid change located in the Dynein heavy chain, tail domain (IPR013594) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant leads to exon 13 skipping, resulting in premature protein truncation (example: Hofner_2006). The variant allele was found at a frequency of 2.2e-05 in 231028 control chromosomes (gnomAD). c.1730G>C has been reported in the literature in an individual affected with Primary ciliary dyskinesia (in heterozygous state), characterized by defective outer dynein arms on electron microscopy (example: Hofner_2006). The following publication has been ascertained in the context of this evaluation (PMID: 16627867). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Primary ciliary dyskinesia

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2016	The c.1730G>C variant (also known as p.R577T), located in coding exon 13 of the DNAH5 gene, results from a G to C substitution at nucleotide position 1730. The amino acid change results in arginine to threonine at codon 577, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 13, which makes it likely to have some effect on normal mRNA splicing. This variant was detected in a patient with primary ciliary dyskinesia (characterized by defective outer dynein arms on electron microscopy). A second alteration was not detected; however, studies of the patient's respiratory epithelial cells showed exon 13 skipping, resulting in premature protein truncation (Hornef N, Am. J. Respir. Crit. Care Med. 2006 Jul; 174(2):120-6). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6488 samples (12976 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2023	This sequence change affects codon 577 of the DNAH5 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DNAH5 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs397515541, gnomAD 0.004%). This variant has been observed in individual(s) with clinical features of primary ciliary dyskinesia (PMID: 16627867; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 65637). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 13 and introduces a premature termination codon (PMID: 16627867). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 12, 2024

Functional studies and in silico splice predictors suggest that the this variant causes skipping of exon 13 (PMID: 16627867); This variant is associated with the following publications: (PMID: 34758253, 16627867, 31879361) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.41

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.086

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.14

Sift

Uncertain

0.014

Polyphen

0.11

Vest4

0.60

MutPred

0.53

Loss of MoRF binding (P = 0.0176);

MVP

0.70

MPC

0.24

ClinPred

0.67

GERP RS

4.9

Varity_R

0.62

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.89

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.89

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over