rs148891849

Variant names:

• chr5-13841895-G-A
• rs148891849
• NM_001369.3:c.5281C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-13841895-G-A
• chr5-13841895-G-C
• chr5-13841895-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001369.3(DNAH5):​c.5281C>T​(p.Arg1761*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000065 in 984,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1761R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAH5 NM_001369.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.99
• Publications: 5 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-13841895-G-A is Pathogenic according to our data. Variant chr5-13841895-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 220475.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.5281C>T	p.Arg1761*	stop_gained	Exon 33 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.5281C>T	p.Arg1761*	stop_gained	Exon 33 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.5236C>T	p.Arg1746*	stop_gained	Exon 33 of 79	ENSP00000505288.1	A0A7P0Z455

Frequencies

GnomAD3 genomes AF: 0.0000184 AC: 2 AN: 108870 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000357

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000171

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000216 AC: 5 AN: 231214 AF XY: 0.0000159

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 FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000650 AC: 64 AN: 984892 Hom.: 0 Cov.: 26 AF XY: 0.0000616 AC XY: 31 AN XY: 502840

African (AFR) AF: 0.0000425 AC: 1 AN: 23556

American (AMR) AF: 0.00 AC: 0 AN: 40024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19594

East Asian (EAS) AF: 0.00 AC: 0 AN: 28276

South Asian (SAS) AF: 0.0000134 AC: 1 AN: 74572

European-Finnish (FIN) AF: 0.0000226 AC: 1 AN: 44288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4064

European-Non Finnish (NFE) AF: 0.0000846 AC: 60 AN: 709502

Other (OTH) AF: 0.0000244 AC: 1 AN: 41016

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000184 AC: 2 AN: 108870 Hom.: 0 Cov.: 25 AF XY: 0.0000203 AC XY: 1 AN XY: 49190

African (AFR) AF: 0.0000357 AC: 1 AN: 28040

American (AMR) AF: 0.00 AC: 0 AN: 7554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3172

East Asian (EAS) AF: 0.00 AC: 0 AN: 3602

South Asian (SAS) AF: 0.00 AC: 0 AN: 3078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 98

European-Non Finnish (NFE) AF: 0.0000171 AC: 1 AN: 58320

Other (OTH) AF: 0.00 AC: 0 AN: 1406

Alfa AF: 0.00 Hom.: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Primary ciliary dyskinesia (3)
2	-	-	Primary ciliary dyskinesia 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		4.0
Vest4		0.95
GERP RS		5.1
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -25

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

Other links and lift over

dbSNP: rs148891849; hg19: chr5-13842004; COSMIC: COSV54258035;