rs1554255966

chr7-775030-ATGCCCCA-ACCACCCTGGGT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017802.4(DNAAF5):c.2108_2114delinsCCACCCTGGGT(p.Met703ThrfsTer46) variant causes a frameshift 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.14

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 454858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.2108_2114delinsCCACCCTGGGT	p.Met703ThrfsTer46	frameshift_variant	11/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.2108_2114delinsCCACCCTGGGT	p.Met703ThrfsTer46	frameshift_variant	11/12
DNAAF5	NR_075098.2	n.2068_2074delinsCCACCCTGGGT		non_coding_transcript_exon_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.2108_2114delinsCCACCCTGGGT	p.Met703ThrfsTer46	frameshift_variant	11/13	1	NM_017802.4	P1
DNAAF5	ENST00000403952.3	c.383_389delinsCCACCCTGGGT	p.Met128ThrfsTer46	frameshift_variant	4/6	1
DNAAF5	ENST00000440747.5	c.1512_1518delinsCCACCCTGGGT	p.Met505ThrfsTer46	frameshift_variant	11/13	2

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 18 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 03, 2022

- -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change creates a premature translational stop signal (p.Met703Thrfs*46) in the DNAAF5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAAF5 are known to be pathogenic (PMID: 24307375, 25232951). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DNAAF5-related conditions. ClinVar contains an entry for this variant (Variation ID: 454858). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554255966; hg19: chr7-814668;