rs61761345

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_130810.4(DNAAF4):c.1249G>T(p.Glu417*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,611,952 control chromosomes in the GnomAD database, including 13,397 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 4178 hom., cov: 32)

Exomes 𝑓: 0.096 ( 9219 hom. )

Consequence

DNAAF4
NM_130810.4 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.351

Publications

56 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0111 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 15-55430684-C-A is Benign according to our data. Variant chr15-55430684-C-A is described in ClinVar as Benign. ClinVar VariationId is 2136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 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	UniProt
DNAAF4	NM_130810.4	MANE Select	c.1249G>T	p.Glu417*	stop_gained	Exon 10 of 10	NP_570722.2	Q8WXU2-1
DNAAF4	NM_001033559.3		c.*12G>T		3_prime_UTR	Exon 9 of 9	NP_001028731.1	Q8WXU2-3
DNAAF4	NM_001033560.2		c.1047+4221G>T		intron	N/A	NP_001028732.1	Q8WXU2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAAF4	ENST00000321149.7	TSL:1 MANE Select	c.1249G>T	p.Glu417*	stop_gained	Exon 10 of 10	ENSP00000323275.3	Q8WXU2-1
DNAAF4	ENST00000457155.6	TSL:1	c.*12G>T		3_prime_UTR	Exon 8 of 8	ENSP00000402640.2	Q8WXU2-3
DNAAF4	ENST00000448430.6	TSL:1	c.1047+4221G>T		intron	N/A	ENSP00000403412.2	Q8WXU2-2

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27025

AN:

151988

Hom.:

4172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.421

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.102

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.0849

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0852

Gnomad OTH

AF:

0.148

GnomAD2 exomes

AF:

0.104

AC:

26061

AN:

250812

AF XY:

0.102

show subpopulations

Gnomad AFR exome

AF:

0.426

Gnomad AMR exome

AF:

0.0551

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.00805

Gnomad FIN exome

AF:

0.0793

Gnomad NFE exome

AF:

0.0860

Gnomad OTH exome

AF:

0.0962

GnomAD4 exome

AF:

0.0964

AC:

140755

AN:

1459846

Hom.:

9219

Cov.:

AF XY:

0.0965

AC XY:

70106

AN XY:

726294

show subpopulations

African (AFR)

AF:

0.438

AC:

14621

AN:

33418

American (AMR)

AF:

0.0612

AC:

2730

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

3241

AN:

26070

East Asian (EAS)

AF:

0.00551

AC:

218

AN:

39534

South Asian (SAS)

AF:

0.127

AC:

10932

AN:

86008

European-Finnish (FIN)

AF:

0.0823

AC:

4378

AN:

53184

Middle Eastern (MID)

AF:

0.123

AC:

701

AN:

5700

European-Non Finnish (NFE)

AF:

0.0876

AC:

97333

AN:

1111018

Other (OTH)

AF:

0.110

AC:

6601

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

5718

11437

17155

22874

28592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3812

7624

11436

15248

19060

<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:

0.178

AC:

27065

AN:

152106

Hom.:

4178

Cov.:

AF XY:

0.175

AC XY:

13000

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.421

AC:

17435

AN:

41446

American (AMR)

AF:

0.101

AC:

1550

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

425

AN:

3472

East Asian (EAS)

AF:

0.0108

AC:

AN:

5178

South Asian (SAS)

AF:

0.114

AC:

551

AN:

4818

European-Finnish (FIN)

AF:

0.0849

AC:

899

AN:

10584

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0852

AC:

5796

AN:

68010

Other (OTH)

AF:

0.147

AC:

312

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

954

1909

2863

3818

4772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.112

Hom.:

5065

Bravo

AF:

0.188

TwinsUK

AF:

0.0890

AC:

330

ALSPAC

AF:

0.0825

AC:

318

ESP6500AA

AF:

0.416

AC:

1825

ESP6500EA

AF:

0.0892

AC:

765

ExAC

AF:

0.112

AC:

13636

Asia WGS

AF:

0.0840

AC:

291

AN:

3474

EpiCase

AF:

0.0916

EpiControl

AF:

0.0925

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Primary ciliary dyskinesia 25 (1)

Dyslexia, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.33

PhyloP100

0.35

Vest4

0.38

GERP RS

4.7

Mutation Taster

=177/23

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