rs16976354

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_130810.4(DNAAF4):c.114C>A(p.Asn38Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,942 control chromosomes in the GnomAD database, including 1,552 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 786 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 766 hom. )

Consequence

DNAAF4
NM_130810.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0290

Publications

9 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011978745).

BP6

Variant 15-55498216-G-T is Benign according to our data. Variant chr15-55498216-G-T is described in ClinVar as Benign. ClinVar VariationId is 416510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130810.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF4	NM_130810.4	MANE Select	c.114C>A	p.Asn38Lys	missense	Exon 2 of 10	NP_570722.2
DNAAF4	NM_001033560.2		c.114C>A	p.Asn38Lys	missense	Exon 2 of 9	NP_001028732.1
DNAAF4	NM_001033559.3		c.114C>A	p.Asn38Lys	missense	Exon 2 of 9	NP_001028731.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF4	ENST00000321149.7	TSL:1 MANE Select	c.114C>A	p.Asn38Lys	missense	Exon 2 of 10	ENSP00000323275.3
DNAAF4	ENST00000448430.6	TSL:1	c.114C>A	p.Asn38Lys	missense	Exon 1 of 8	ENSP00000403412.2
DNAAF4	ENST00000457155.6	TSL:1	c.114C>A	p.Asn38Lys	missense	Exon 1 of 8	ENSP00000402640.2

Frequencies

GnomAD3 genomes

AF:

0.0548

AC:

8345

AN:

152198

Hom.:

784

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0363

GnomAD2 exomes

AF:

0.0139

AC:

3492

AN:

250676

AF XY:

0.0100

show subpopulations

Gnomad AFR exome

AF:

0.197

Gnomad AMR exome

AF:

0.00685

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00573

GnomAD4 exome

AF:

0.00548

AC:

8008

AN:

1461626

Hom.:

766

Cov.:

AF XY:

0.00465

AC XY:

3379

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.204

AC:

6834

AN:

33462

American (AMR)

AF:

0.00790

AC:

353

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.000278

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000107

AC:

119

AN:

1111906

Other (OTH)

AF:

0.0109

AC:

661

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

354

708

1061

1415

1769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

204

408

612

816

1020

<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:

0.0549

AC:

8358

AN:

152316

Hom.:

786

Cov.:

AF XY:

0.0532

AC XY:

3961

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.194

AC:

8050

AN:

41556

American (AMR)

AF:

0.0140

AC:

214

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68036

Other (OTH)

AF:

0.0360

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

352

704

1057

1409

1761

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0215

Hom.:

629

Bravo

AF:

0.0627

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.194

AC:

849

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0176

AC:

2132

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0019

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.070

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.0

PhyloP100

0.029

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.13

REVEL

Benign

0.11

Sift

Benign

0.30

Sift4G

Benign

0.58

Polyphen

0.82

Vest4

0.23

MutPred

0.20

Gain of ubiquitination at N38 (P = 0.0211)

MPC

0.075

ClinPred

0.0020

GERP RS

-1.6

PromoterAI

0.012

Neutral

(source)

Varity_R

0.13

gMVP

0.17

Mutation Taster

=97/3

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over