rs1057519569

Variant names:

• chrX-107222767-C-T
• rs1057519569
• NM_173494.2:c.355C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_173494.2(DNAAF6):​c.355C>T​(p.Gln119*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: DNAAF6 NM_173494.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.541
• Publications: 4 publications found

Genes affected

DNAAF6 (HGNC:28570): (dynein axonemal assembly factor 6) Enables dynein intermediate chain binding activity. Involved in flagellated sperm motility; inner dynein arm assembly; and outer dynein arm assembly. Located in trans-Golgi network. Implicated in primary ciliary dyskinesia 36. [provided by Alliance of Genome Resources, Apr 2022]

DNAAF6 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 36, X-linked

  Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 X-107222767-C-T is Pathogenic according to our data. Variant chrX-107222767-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 375563.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173494.2. 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
	DNAAF6	NM_173494.2	MANE Select	c.355C>T	p.Gln119*	stop_gained	Exon 5 of 7	NP_775765.1
	DNAAF6	NM_001169154.2		c.355C>T	p.Gln119*	stop_gained	Exon 6 of 8	NP_001162625.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF6	ENST00000372453.8	TSL:1 MANE Select	c.355C>T	p.Gln119*	stop_gained	Exon 5 of 7	ENSP00000361531.3
	DNAAF6	ENST00000336387.4	TSL:5	c.355C>T	p.Gln119*	stop_gained	Exon 5 of 7	ENSP00000337757.4
	DNAAF6	ENST00000535523.6	TSL:5	c.355C>T	p.Gln119*	stop_gained	Exon 6 of 8	ENSP00000441930.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Ciliary dyskinesia, primary, 36, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.71	D
PhyloP100		0.54
Vest4		0.39
GERP RS		2.1
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.40		Position offset: -22

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

Other links and lift over

dbSNP: rs1057519569; hg19: chrX-106465997;