rs1554020311

Variant names:

• chr5-13717499-T-C
• rs1554020311
• NM_001369.3:c.12521A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001369.3(DNAH5):​c.12521A>G​(p.Asp4174Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D4174D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.12521A>G	p.Asp4174Gly	missense_variant	Exon 73 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.12521A>G	p.Asp4174Gly	missense_variant	Exon 73 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.12476A>G	p.Asp4159Gly	missense_variant	Exon 73 of 79			ENSP00000505288.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with glycine at codon 4174 of the DNAH5 protein (p.Asp4174Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DNAH5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		8.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.22
Sift	Uncertain	0.013	D
Polyphen		0.060	B
Vest4		0.60
MutPred		0.46		Gain of catalytic residue at S4176 (P = 0.0179);
MVP		0.60
MPC		0.46
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.59
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs1554020311; hg19: chr5-13717608;