dbSNP rs114601492: DNAAF3:p.Val469Met (chr19-55159283-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001256714.1(DNAAF3):c.1606G>A(p.Val536Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,078 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 19 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 15 hom. )

Consequence

DNAAF3
NM_001256714.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.11

Publications

1 publications found

Variant links:

Genes affected

DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

DNAAF3 links:

ENSG00000267110 (HGNC:):

ENSG00000267110 links:

DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

DNAAF3-AS1 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=0.002953142).

BP6

Variant 19-55159283-C-T is Benign according to our data. Variant chr19-55159283-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00807 (1230/152324) while in subpopulation AFR AF = 0.028 (1165/41564). AF 95% confidence interval is 0.0267. There are 19 homozygotes in GnomAd4. There are 586 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256714.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF3	NM_001256715.2	MANE Select	c.1405G>A	p.Val469Met	missense	Exon 12 of 12	NP_001243644.1
DNAAF3	NM_001256714.1		c.1606G>A	p.Val536Met	missense	Exon 12 of 12	NP_001243643.1
DNAAF3	NM_178837.4		c.1546G>A	p.Val516Met	missense	Exon 12 of 12	NP_849159.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF3	ENST00000524407.7	TSL:1 MANE Select	c.1405G>A	p.Val469Met	missense	Exon 12 of 12	ENSP00000432046.3
DNAAF3	ENST00000455045.5	TSL:1	c.1243G>A	p.Val415Met	missense	Exon 12 of 12	ENSP00000394343.1
DNAAF3	ENST00000528412.5	TSL:1	n.*1193G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000433826.2

Frequencies

GnomAD3 genomes

AF:

0.00807

AC:

1228

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0281

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

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:

0.0000294

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00212

AC:

529

AN:

249320

AF XY:

0.00166

show subpopulations

Gnomad AFR exome

AF:

0.0303

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.000779

AC:

1138

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000652

AC XY:

474

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0284

AC:

951

AN:

33480

American (AMR)

AF:

0.00152

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1112006

Other (OTH)

AF:

0.00152

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00807

AC:

1230

AN:

152324

Hom.:

Cov.:

AF XY:

0.00787

AC XY:

586

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0280

AC:

1165

AN:

41564

American (AMR)

AF:

0.00327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00337

Hom.:

Bravo

AF:

0.00905

ESP6500AA

AF:

0.0250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00258

AC:

312

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Primary ciliary dyskinesia (2)

Dilated Cardiomyopathy, Recessive (1)

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome (1)

Familial restrictive cardiomyopathy (1)

Hypertrophic cardiomyopathy (1)

Primary ciliary dyskinesia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0039

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.90

PhyloP100

-1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.51

REVEL

Benign

0.070

Sift

Benign

0.060

Sift4G

Uncertain

0.054

Polyphen

0.96

Vest4

0.12

MVP

0.13

MPC

0.67

ClinPred

0.027

GERP RS

-0.29

Varity_R

0.019

gMVP

0.27

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over