X-107218863-G-A

Position:

• chrX-107218863-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_173494.2(DNAAF6):​c.227-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DNAAF6 NM_173494.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.33

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-107218863-G-A is Pathogenic according to our data. Variant chrX-107218863-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2708214.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF6	NM_173494.2	c.227-1G>A		splice_acceptor_variant, intron_variant		ENST00000372453.8	NP_775765.1
DNAAF6	NM_001169154.2	c.227-1G>A		splice_acceptor_variant, intron_variant			NP_001162625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF6	ENST00000372453.8	c.227-1G>A		splice_acceptor_variant, intron_variant		1	NM_173494.2	ENSP00000361531.3
DNAAF6	ENST00000336387.4	c.227-1G>A		splice_acceptor_variant, intron_variant		5		ENSP00000337757.4
DNAAF6	ENST00000535523.6	c.227-1G>A		splice_acceptor_variant, intron_variant		5		ENSP00000441930.1
DNAAF6	ENST00000688816.1	c.227-1G>A		splice_acceptor_variant, intron_variant				ENSP00000508655.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change affects an acceptor splice site in intron 4 of the PIH1D3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIH1D3 are known to be pathogenic (PMID: 28041644, 28176794). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of PIH1D3-related conditions (Invitae). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.97	D
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: 17
DS_AL_spliceai		1.0		Position offset: 1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-106462093;