rs1060501468

chr5-13841784-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001369.3(DNAH5):c.5392T>C(p.Ser1798Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.349

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.5392T>C	p.Ser1798Pro	missense_variant	33/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.5392T>C	p.Ser1798Pro	missense_variant	33/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.5347T>C	p.Ser1783Pro	missense_variant	33/79			A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 13, 2021	This sequence change replaces serine with proline at codon 1798 of the DNAH5 protein (p.Ser1798Pro). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of DNAH5-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 407256). 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: "Tolerated"; 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 11, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.29
Sift	Benign	0.21	T
Polyphen		0.087	B
Vest4		0.62
MutPred		0.55		Gain of glycosylation at S1798 (P = 0.0596);
MVP		0.65
MPC		0.36
ClinPred		0.86	D
GERP RS		1.8
Varity_R		0.88
gMVP		0.63

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: rs1060501468; hg19: chr5-13841893;