chr7-775031-TGCCCCA-CCACCCTGGGT

Variant names:

• chr7-775031-TGCCCCA-CCACCCTGGGT
• rs1554255966
• NM_017802.4:c.2108_2114delTGCCCCAinsCCACCCTGGGT

Variant summary

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

The NM_017802.4(DNAAF5):​c.2108_2114delTGCCCCAinsCCACCCTGGGT​(p.Met703ThrfsTer46) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAAF5 NM_017802.4 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.14
• Publications: 0 publications found

Genes affected

DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

DNAAF5 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 18

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, 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 7-775031-TGCCCCA-CCACCCTGGGT is Pathogenic according to our data. Variant chr7-775031-TGCCCCA-CCACCCTGGGT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 454858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017802.4. 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
	DNAAF5	NM_017802.4	MANE Select	c.2108_2114delTGCCCCAinsCCACCCTGGGT	p.Met703ThrfsTer46	frameshift missense	Exon 11 of 13	NP_060272.3
	DNAAF5	NR_075098.2		n.2068_2074delTGCCCCAinsCCACCCTGGGT		non_coding_transcript_exon	Exon 11 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.2108_2114delTGCCCCAinsCCACCCTGGGT	p.Met703ThrfsTer46	frameshift missense	Exon 11 of 13	ENSP00000297440.6
	DNAAF5	ENST00000403952.3	TSL:1	c.383_389delTGCCCCAinsCCACCCTGGGT	p.Met128ThrfsTer46	frameshift missense	Exon 4 of 6	ENSP00000384884.3
	DNAAF5	ENST00000852634.1		c.2189_2195delTGCCCCAinsCCACCCTGGGT	p.Met730ThrfsTer46	frameshift missense	Exon 12 of 14	ENSP00000522693.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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 18 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1

Splicing

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

Other links and lift over

dbSNP: rs1554255966; hg19: chr7-814668;