5-13700794-G-T

Position:

• chr5-13700794-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001369.3(DNAH5):​c.13569C>A​(p.Asp4523Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000256 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 0.261

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0079782605).
• BP6: Variant 5-13700794-G-T is Benign according to our data. Variant chr5-13700794-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163131.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.13569C>A	p.Asp4523Glu	missense_variant	78/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.13569C>A	p.Asp4523Glu	missense_variant	78/79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.13524C>A	p.Asp4508Glu	missense_variant	78/79			ENSP00000505288.1
DNAH5	ENST00000683611.1	n.902C>A		non_coding_transcript_exon_variant	4/5

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251334 Hom.: 0 AF XY: 0.000375 AC XY: 51 AN XY: 135828

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.000199 AC XY: 145 AN XY: 727234

Gnomad4 AFR exome AF: 0.00317

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74422

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00231

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: 0.000396 Hom.: 0

Bravo AF: 0.00108

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 3 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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	Revvity Omics, Revvity	Feb 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 11, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Primary ciliary dyskinesia Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 15, 2017	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Asp4523Glu in exon 78 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (15/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs151080414). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.23
DANN	Benign	0.34
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.53	N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Polyphen		0.040	B
Vest4		0.30
MutPred		0.34		Loss of sheet (P = 0.0817);
MVP		0.28
MPC		0.40
ClinPred		0.016	T
GERP RS		-6.7
Varity_R		0.073
gMVP		0.38

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: rs151080414; hg19: chr5-13700903;