chr5-13902136-G-T

Variant names:

• chr5-13902136-G-T
• rs139160176
• NM_001369.3:c.1647C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001369.3(DNAH5):​c.1647C>A​(p.Asn549Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAH5 NM_001369.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.451

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.1647C>A	p.Asn549Lys	missense_variant, splice_region_variant	Exon 13 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.1647C>A	p.Asn549Lys	missense_variant, splice_region_variant	Exon 13 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.1602C>A	p.Asn534Lys	missense_variant, splice_region_variant	Exon 13 of 79			ENSP00000505288.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447250 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 720184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.51		Gain of ubiquitination at N549 (P = 0.0337);
MVP		0.42
MPC		0.44
ClinPred		0.36	T
GERP RS		-1.1
Varity_R		0.11
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139160176; hg19: chr5-13902245;