15-55467043-AT-ATT

Position:

• chr15-55467043-AT-ATT

Variant summary

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

The NM_130810.4(DNAAF4):​c.523dupA​(p.Ile175fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,548,996 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 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: DNAAF4 NM_130810.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.645

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-CCPG1 (HGNC:):

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 15-55467043-A-AT is Pathogenic according to our data. Variant chr15-55467043-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.523dupA	p.Ile175fs	frameshift_variant	5/10	ENST00000321149.7	NP_570722.2
DNAAF4	NM_001033560.2	c.523dupA	p.Ile175fs	frameshift_variant	5/9		NP_001028732.1
DNAAF4	NM_001033559.3	c.523dupA	p.Ile175fs	frameshift_variant	5/9		NP_001028731.1
DNAAF4-CCPG1	NR_037923.1	n.778dupA		non_coding_transcript_exon_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.523dupA	p.Ile175fs	frameshift_variant	5/10	1	NM_130810.4	ENSP00000323275.3

Frequencies

GnomAD3 genomes AF: 0.0000333 AC: 5 AN: 150034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

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: 0.0000593

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000672 AC: 94 AN: 1398962 Hom.: 0 Cov.: 32 AF XY: 0.0000737 AC XY: 51 AN XY: 692128

Gnomad4 AFR exome AF: 0.0000655

Gnomad4 AMR exome AF: 0.000170

Gnomad4 ASJ exome AF: 0.0000399

Gnomad4 EAS exome AF: 0.0000555

Gnomad4 SAS exome AF: 0.000142

Gnomad4 FIN exome AF: 0.0000199

Gnomad4 NFE exome AF: 0.0000629

Gnomad4 OTH exome AF: 0.0000520

GnomAD4 genome AF: 0.0000333 AC: 5 AN: 150034 Hom.: 0 Cov.: 32 AF XY: 0.0000410 AC XY: 3 AN XY: 73186

Gnomad4 AFR AF: 0.0000245

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: 0.0000593

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000642

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2020	This sequence change creates a premature translational stop signal (p.Ile175Asnfs*15) in the DNAAF4 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with DNAAF4-related disease. Loss-of-function variants in DNAAF4 are known to be pathogenic (PMID: 23872636). For these reasons, this variant has been classified as Pathogenic. -

Primary ciliary dyskinesia 25 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 14, 2022

ACMG classification criteria: PVS1 very strong, PM2 supporting -

DNAAF4-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2023

The DNAAF4 c.523dupA variant is predicted to result in a frameshift and premature protein termination (p.Ile175Asnfs*15). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-55759241-A-AT). Frameshift variants in DNAAF4 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs751610886; hg19: chr15-55759241;