rs147499872

chr5-13916424-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001369.3(DNAH5):c.1121T>C(p.Ile374Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,558,784 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I374I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00059 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 B:1
• Conservation: PhyloP100: 9.03

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21734911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.1121T>C	p.Ile374Thr	missense_variant	9/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.1121T>C	p.Ile374Thr	missense_variant	9/79	1	NM_001369.3	P4

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152012 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000751 AC: 188 AN: 250334 Hom.: 0 AF XY: 0.000820 AC XY: 111 AN XY: 135378

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.00131 AC: 1839 AN: 1406654 Hom.: 4 Cov.: 24 AF XY: 0.00123 AC XY: 867 AN XY: 702782

Gnomad4 AFR exome AF: 0.000186

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000705

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.000617

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152130 Hom.: 1 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74380

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00120 Hom.: 0

Bravo AF: 0.000638

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.00115

EpiControl AF: 0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 3 Pathogenic:1 Uncertain:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 10, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 11, 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	Counsyl	Sep 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 15, 2021	- -

Primary ciliary dyskinesia Uncertain:3 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 29, 2019	The p.I374T variant (also known as c.1121T>C), located in coding exon 9 of the DNAH5 gene, results from a T to C substitution at nucleotide position 1121. The isoleucine at codon 374 is replaced by threonine, an amino acid with similar properties. This variant was identified in a child with primary ciliary dyskinesia and situs inversus in conjunction with another DNAH5 variant in trans (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106). Based on data from gnomAD, the C allele has an overall frequency of approximately 0.071% (201/281530) total alleles studied. The highest observed frequency was 0.162% (82/50458) of Northwestern European alleles. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Apr 18, 2019	- -

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2017	The I374T variant in the DNAH5 gene has been reported previously in trans with another DNAH5 variant in an individual with primary ciliary dyskinesia (Knowles et al., 2013). The I374T variant is observed in 63/65,796 (0.096%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The I374T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I374T as a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Polyphen		0.070	B
Vest4		0.83
MVP		0.68
MPC		0.12
ClinPred		0.097	T
GERP RS		5.3
Varity_R		0.54
gMVP		0.70

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: rs147499872; hg19: chr5-13916533;