NM_001369.3:c.5118C>G

Variant names:

• chr5-13844990-G-C
• rs1554074565
• NM_001369.3:c.5118C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001369.3(DNAH5):​c.5118C>G​(p.Tyr1706*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAH5 NM_001369.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.56
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-13844990-G-C is Pathogenic according to our data. Variant chr5-13844990-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 454780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.5118C>G	p.Tyr1706*	stop_gained	Exon 32 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.5118C>G	p.Tyr1706*	stop_gained	Exon 32 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.5073C>G	p.Tyr1691*	stop_gained	Exon 32 of 79	ENSP00000505288.1	A0A7P0Z455

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000139 AC: 2 AN: 1440834 Hom.: 0 Cov.: 38 AF XY: 0.00000279 AC XY: 2 AN XY: 717114

African (AFR) AF: 0.00 AC: 0 AN: 33028

American (AMR) AF: 0.00 AC: 0 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 39026

South Asian (SAS) AF: 0.00 AC: 0 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1096672

Other (OTH) AF: 0.00 AC: 0 AN: 59030

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.014
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		1.6
Vest4		0.94
GERP RS		2.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1554074565; hg19: chr5-13845099;