rs1060503094

Positions:

chr15-55430708-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000321149.7(DNAAF4):c.1225A>T(p.Ile409Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I409I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

DNAAF4
ENST00000321149.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.54

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNAAF4	NM_130810.4 linkuse as main transcript	c.1225A>T	p.Ile409Phe	missense_variant	10/10	ENST00000321149.7	NP_570722.2
DNAAF4-CCPG1	NR_037923.1 linkuse as main transcript	n.1408+1789A>T		intron_variant, non_coding_transcript_variant
DNAAF4	NM_001033559.3 linkuse as main transcript	c.1119A>T	p.Arg373Ser	missense_variant	9/9		NP_001028731.1
DNAAF4	NM_001033560.2 linkuse as main transcript	c.1047+4197A>T		intron_variant			NP_001028732.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7 linkuse as main transcript	c.1225A>T	p.Ile409Phe	missense_variant	10/10	1	NM_130810.4	ENSP00000323275	P1	Q8WXU2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251284

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461106

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2016

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DYX1C1-related disease. This sequence change replaces isoleucine with phenylalanine at codon 409 of the DYX1C1 protein (p.Ile409Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;.

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;N;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.0

.;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.014

.;D

Sift4G

Uncertain

0.014

D;D

Polyphen

1.0

D;D

Vest4

0.83

MutPred

0.68

Gain of ubiquitination at K408 (P = 0.0882);Gain of ubiquitination at K408 (P = 0.0882);

MVP

0.57

MPC

0.38

ClinPred

0.92

GERP RS

5.6

Varity_R

0.33

gMVP

0.66

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