chr19-55161694-G-GGCGTC

Variant names:

• chr19-55161694-G-GGCGTC
• rs1060502831
• NM_001256715.2:c.607_611dupGACGC

Variant summary

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

The NM_001256715.2(DNAAF3):​c.607_611dupGACGC​(p.Arg205ThrfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000216 in 1,388,600 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. A204A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: DNAAF3 NM_001256715.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.40
• Publications: 0 publications found

Genes affected

DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

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 19-55161694-G-GGCGTC is Pathogenic according to our data. Variant chr19-55161694-G-GGCGTC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 410288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256715.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF3	NM_001256715.2	MANE Select	c.607_611dupGACGC	p.Arg205ThrfsTer13	frameshift	Exon 6 of 12	NP_001243644.1
	DNAAF3	NM_001256714.1		c.811_815dupGACGC	p.Arg273ThrfsTer13	frameshift	Exon 6 of 12	NP_001243643.1
	DNAAF3	NM_178837.4		c.748_752dupGACGC	p.Arg252ThrfsTer13	frameshift	Exon 6 of 12	NP_849159.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF3	ENST00000524407.7	TSL:1 MANE Select	c.607_611dupGACGC	p.Arg205ThrfsTer13	frameshift	Exon 6 of 12	ENSP00000432046.3
	DNAAF3	ENST00000455045.5	TSL:1	c.445_449dupGACGC	p.Arg151ThrfsTer13	frameshift	Exon 6 of 12	ENSP00000394343.1
	DNAAF3	ENST00000528412.5	TSL:1	n.*395_*399dupGACGC		non_coding_transcript_exon	Exon 6 of 12	ENSP00000433826.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000728 AC: 1 AN: 137368 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000947

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1388600 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 685208

African (AFR) AF: 0.00 AC: 0 AN: 31466

American (AMR) AF: 0.00 AC: 0 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25104

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35692

South Asian (SAS) AF: 0.00 AC: 0 AN: 79120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4106

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078546

Other (OTH) AF: 0.0000173 AC: 1 AN: 57702

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Primary ciliary dyskinesia (1)
1	-	-	Primary ciliary dyskinesia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1060502831; hg19: chr19-55673062;