5-13810210-G-T

Variant names:

• chr5-13810210-G-T
• rs1554058794
• NM_001369.3:c.7458C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001369.3(DNAH5):​c.7458C>A​(p.Phe2486Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F2486F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_001369.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.7458C>A	p.Phe2486Leu	missense	Exon 45 of 79	NP_001360.1	Q8TE73

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.7458C>A	p.Phe2486Leu	missense	Exon 45 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.7413C>A	p.Phe2471Leu	missense	Exon 45 of 79	ENSP00000505288.1	A0A7P0Z455
	DNAH5	ENST00000512443.1	TSL:3	n.314C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398146 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 689690

African (AFR) AF: 0.00 AC: 0 AN: 31578

American (AMR) AF: 0.00 AC: 0 AN: 35734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25144

East Asian (EAS) AF: 0.00 AC: 0 AN: 35748

South Asian (SAS) AF: 0.00 AC: 0 AN: 79252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078856

Other (OTH) AF: 0.00 AC: 0 AN: 57964

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		1.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.69		Gain of helix (P = 0.062)
MVP		0.66
MPC		0.16
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.75
gMVP		0.81
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554058794; hg19: chr5-13810319;