15-55439503-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_130810.4(DNAAF4):c.862A>G(p.Lys288Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000118 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

DNAAF4
NM_130810.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.94

Publications

0 publications found

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:43019): (DNAAF4-CCPG1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring dyslexia susceptibility 1 candidate 1 (DYX1C1) and cell cycle progression 1 (CCPG1) genes on chromosome 15. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

DNAAF4-CCPG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025500715).

BP6

Variant 15-55439503-T-C is Benign according to our data. Variant chr15-55439503-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 410959.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNAAF4	NM_130810.4 link	c.862A>G	p.Lys288Glu	missense_variant	Exon 7 of 10	ENST00000321149.7	NP_570722.2
DNAAF4	NM_001033560.2 link	c.862A>G	p.Lys288Glu	missense_variant	Exon 7 of 9		NP_001028732.1
DNAAF4	NM_001033559.3 link	c.862A>G	p.Lys288Glu	missense_variant	Exon 7 of 9		NP_001028731.1
DNAAF4-CCPG1	NR_037923.1 link	n.1117A>G		non_coding_transcript_exon_variant	Exon 6 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7 link	c.862A>G	p.Lys288Glu	missense_variant	Exon 7 of 10	1	NM_130810.4	ENSP00000323275.3

Frequencies

GnomAD3 genomes

AF:

0.000716

AC:

109

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00191

GnomAD2 exomes

AF:

0.000151

AC:

AN:

251416

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00215

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111962

Other (OTH)

AF:

0.0000828

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000715

AC:

109

AN:

152344

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00248

AC:

103

AN:

41598

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000801

ESP6500AA

AF:

0.00319

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

DNAAF4-related disorder

Uncertain:1

Jan 10, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DNAAF4 c.862A>G variant is predicted to result in the amino acid substitution p.Lys288Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.23% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-55731701-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0043

.;.;T;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.91

D;D;D;.

M_CAP

Benign

0.027

MetaRNN

Benign

0.026

T;T;T;T

MetaSVM

Benign

-0.34

PhyloP100

4.9

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.031

D;D;D;D

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.97

D;B;P;P

Vest4

0.59

MVP

0.85

MPC

0.31

ClinPred

0.12

GERP RS

5.1

Varity_R

0.32

gMVP

0.46

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over