Variant rs751610886 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_130810.4(DNAAF4):c.523del(p.Ile175PhefsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,546,014 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

DNAAF4
NM_130810.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.645

Variant links:

Genes affected

DNAAF4 (HGNC:21493): (dynein axonemal assembly factor 4) This gene encodes a tetratricopeptide repeat domain-containing protein. The encoded protein interacts with estrogen receptors and the heat shock proteins, Hsp70 and Hsp90. An homologous protein in rat has been shown to function in neuronal migration in the developing neocortex. A chromosomal translocation involving this gene is associated with a susceptibility to developmental dyslexia. Mutations in this gene are associated with deficits in reading and spelling. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream cell cycle progression 1 (CCPG1) gene. [provided by RefSeq, Mar 2011]

DNAAF4 links:

DNAAF4-CCPG1 (HGNC:):

DNAAF4-CCPG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 15-55467043-AT-A is Pathogenic according to our data. Variant chr15-55467043-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DNAAF4	NM_130810.4 linkuse as main transcript	c.523del	p.Ile175PhefsTer21	frameshift_variant	5/10	ENST00000321149.7
DNAAF4-CCPG1	NR_037923.1 linkuse as main transcript	n.778del		non_coding_transcript_exon_variant	4/16
DNAAF4	NM_001033560.2 linkuse as main transcript	c.523del	p.Ile175PhefsTer21	frameshift_variant	5/9
DNAAF4	NM_001033559.3 linkuse as main transcript	c.523del	p.Ile175PhefsTer21	frameshift_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF4	ENST00000321149.7 linkuse as main transcript	c.523del	p.Ile175PhefsTer21	frameshift_variant	5/10	1	NM_130810.4	P1	Q8WXU2-1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000735

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000166

AC:

232

AN:

1395982

Hom.:

Cov.:

AF XY:

0.000184

AC XY:

127

AN XY:

690550

show subpopulations

Gnomad4 AFR exome

AF:

0.000197

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.000321

Gnomad4 EAS exome

AF:

0.000167

Gnomad4 SAS exome

AF:

0.000533

Gnomad4 FIN exome

AF:

0.000120

Gnomad4 NFE exome

AF:

0.0000917

Gnomad4 OTH exome

AF:

0.000209

GnomAD4 genome

AF:

0.0000200

AC:

AN:

150032

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73190

show subpopulations

Gnomad4 AFR

AF:

0.0000735

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00300

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 01, 2017

The p.Ile175PhefsX21 (NM_130810.3 c.523delA) variant in DNAAF4 has not been prev iously reported in individuals with primary ciliary dyskinesia. This variant has been identified in 0.26% (50/19436) of Latino chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778891601). Alt hough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is pre dicted to cause a frameshift, which alters the protein?s amino acid sequence beg inning at position 175 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the DNAAF4 gene has been associated with primary ciliary dyskinesia. In summary, although additional studies are required to fully establish a null effect on the protein, the p.Ile175PhefsX21 variant i n DNAAF4 gene is likely pathogenic for primary ciliary dyskinesia in an autosoma l recessive manner based on a predicted null effect. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 13, 2016

This sequence change deletes 1 nucleotide from exon 5 of the DYX1C1 mRNA (c.523delA), causing a frameshift at codon 175. This creates a premature translational stop signal (p.Ile175Phefs*21) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in DYX1C1 are known to be pathogenic (PMID: 23872636). For these reasons, this variant has been classified as Pathogenic. -

Dyslexia, susceptibility to, 1;C3809641:Primary ciliary dyskinesia 25

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over