rs746242380

Variant names:

• chr17-44902645-CAGAG-C
• rs746242380
• NM_213607.3:c.566_569delAGAG

Your query was ambiguous. Multiple possible variants found:

• chr17-44902645-CAGAG-C
• chr17-44902645-CAGAG-CAG
• chr17-44902645-CAGAG-CAGAGAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_213607.3(DNAAF19):​c.566_569delAGAG​(p.Glu189AlafsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000229 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E189E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: DNAAF19 NM_213607.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.53
• Publications: 2 publications found

Genes affected

DNAAF19 (HGNC:32700): (coiled-coil domain containing 103) Enables protein homodimerization activity. Involved in axonemal dynein complex assembly; cilium movement; and determination of left/right symmetry. Predicted to be located in axoneme. Predicted to be part of outer dynein arm. Implicated in primary ciliary dyskinesia 17. [provided by Alliance of Genome Resources, Apr 2022]

DNAAF19 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 17

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.224 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 17-44902645-CAGAG-C is Pathogenic according to our data. Variant chr17-44902645-CAGAG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1451307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213607.3. 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
	DNAAF19	NM_213607.3	MANE Select	c.566_569delAGAG	p.Glu189AlafsTer18	frameshift	Exon 4 of 4	NP_998772.1	Q8IW40-1
	DNAAF19	NM_001258395.2		c.566_569delAGAG	p.Glu189AlafsTer18	frameshift	Exon 4 of 4	NP_001245324.1	Q8IW40-1
	DNAAF19	NM_001258396.2		c.566_569delAGAG	p.Glu189AlafsTer18	frameshift	Exon 4 of 4	NP_001245325.1	Q8IW40-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF19	ENST00000417826.3	TSL:1 MANE Select	c.566_569delAGAG	p.Glu189AlafsTer18	frameshift	Exon 4 of 4	ENSP00000391692.2	Q8IW40-1
	DNAAF19	ENST00000410006.6	TSL:2	c.566_569delAGAG	p.Glu189AlafsTer18	frameshift	Exon 4 of 4	ENSP00000387252.1	Q8IW40-1
	DNAAF19	ENST00000357776.6	TSL:2	c.566_569delAGAG	p.Glu189AlafsTer18	frameshift	Exon 4 of 4	ENSP00000350420.2	F8W6J8

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249972 AF XY: 0.0000296

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: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461832 Hom.: 0 AF XY: 0.0000275 AC XY: 20 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111968

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152016 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74240

African (AFR) AF: 0.0000725 AC: 3 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Primary ciliary dyskinesia (1)
1	-	-	Primary ciliary dyskinesia 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.5
Mutation Taster		=40/160	disease causing

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

Other links and lift over

dbSNP: rs746242380; hg19: chr17-42980013; COSMIC: COSV53649956; COSMIC: COSV53649956;