rs142302585

Positions:

• chr5-13809055-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001369.3(DNAH5):​c.7741A>G​(p.Lys2581Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000271 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2581R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.13

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-13809055-T-C is Benign according to our data. Variant chr5-13809055-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525238.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.7741A>G	p.Lys2581Glu	missense_variant	46/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.7741A>G	p.Lys2581Glu	missense_variant	46/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.7696A>G	p.Lys2566Glu	missense_variant	46/79			A1
DNAH5	ENST00000512443.1	n.597A>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000954 AC: 24 AN: 251492 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135920

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: 0.0000327

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000293 AC: 429 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.000297 AC XY: 216 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000361

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jul 25, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D
Polyphen		0.65	P
Vest4		0.61
MVP		0.65
MPC		0.37
ClinPred		0.41	T
GERP RS		5.9
Varity_R		0.72
gMVP		0.76

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: rs142302585; hg19: chr5-13809164;