rs1060503095

Positions:

• chr15-55497815-GGGA-GAG

Variant summary

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

The NM_130810.4(DNAAF4):​c.165_167delinsCT​(p.Pro56SerfsTer2) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAAF4 NM_130810.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.08

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 12 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 15-55497816-GGA-AG is Pathogenic according to our data. Variant chr15-55497816-GGA-AG is described in ClinVar as [Pathogenic]. Clinvar id is 410963.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.165_167delinsCT	p.Pro56SerfsTer2	frameshift_variant	3/10	ENST00000321149.7	NP_570722.2
DNAAF4-CCPG1	NR_037923.1	n.420_422delinsCT		non_coding_transcript_exon_variant	2/16
DNAAF4	NM_001033559.3	c.165_167delinsCT	p.Pro56SerfsTer2	frameshift_variant	3/9		NP_001028731.1
DNAAF4	NM_001033560.2	c.165_167delinsCT	p.Pro56SerfsTer2	frameshift_variant	3/9		NP_001028732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.165_167delinsCT	p.Pro56SerfsTer2	frameshift_variant	3/10	1	NM_130810.4	ENSP00000323275	P1

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

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

Apr 15, 2019

This variant has not been reported in the literature in individuals with DNAAF4-related disease. ClinVar contains an entry for this variant (Variation ID: 410963). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DNAAF4 are known to be pathogenic (PMID: 23872636). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro56Serfs*2) in the  DNAAF4 gene. It is expected to result in an absent or disrupted protein product. -

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: rs1060503095; hg19: chr15-55790014;