Genetic Variant DNAAF19:p.Ala11Pro (chr17-44901029-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_213607.3(DNAAF19):c.31G>C(p.Ala11Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,603,076 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 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 0 hom. )

Consequence

DNAAF19
NM_213607.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.57

Publications

4 publications found

Variant links:

Genes affected

DNAAF19 (HGNC:32700): (coiled-coil domain containing 103) Enables protein homodimerization activity. Involved in axonemal dynein complex assembly; cilium movement; and determination of left/right symmetry. Predicted to be located in axoneme. Predicted to be part of outer dynein arm. Implicated in primary ciliary dyskinesia 17. [provided by Alliance of Genome Resources, Apr 2022]

DNAAF19 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 17
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAAF19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20496407).

BP6

Variant 17-44901029-G-C is Benign according to our data. Variant chr17-44901029-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 955334.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213607.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAAF19	NM_213607.3	MANE Select	c.31G>C	p.Ala11Pro	missense	Exon 2 of 4	NP_998772.1	Q8IW40-1
DNAAF19	NM_001258395.2		c.31G>C	p.Ala11Pro	missense	Exon 2 of 4	NP_001245324.1	Q8IW40-1
DNAAF19	NM_001258396.2		c.31G>C	p.Ala11Pro	missense	Exon 2 of 4	NP_001245325.1	Q8IW40-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAAF19	ENST00000417826.3	TSL:1 MANE Select	c.31G>C	p.Ala11Pro	missense	Exon 2 of 4	ENSP00000391692.2	Q8IW40-1
DNAAF19	ENST00000410006.6	TSL:2	c.31G>C	p.Ala11Pro	missense	Exon 2 of 4	ENSP00000387252.1	Q8IW40-1
DNAAF19	ENST00000357776.6	TSL:2	c.31G>C	p.Ala11Pro	missense	Exon 2 of 4	ENSP00000350420.2	F8W6J8

Frequencies

GnomAD3 genomes

AF:

0.000236

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000456

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000242

AC:

AN:

239728

AF XY:

0.000246

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000115

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000479

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000437

AC:

634

AN:

1450840

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

301

AN XY:

721944

show subpopulations

African (AFR)

AF:

0.0000612

AC:

AN:

32686

American (AMR)

AF:

0.00

AC:

AN:

40774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25756

East Asian (EAS)

AF:

0.0000511

AC:

AN:

39140

South Asian (SAS)

AF:

0.00

AC:

AN:

84208

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000555

AC:

616

AN:

1109238

Other (OTH)

AF:

0.000200

AC:

AN:

59936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<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:

0.000236

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41466

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000327

Hom.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000264

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (2)

Primary ciliary dyskinesia 17 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

0.13

Eigen_PC

Benign

0.075

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.83

M_CAP

Benign

0.076

MetaRNN

Benign

0.20

MetaSVM

Uncertain

0.064

MutationAssessor

Uncertain

2.8

PhyloP100

3.6

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.42

Sift

Benign

0.066

Sift4G

Benign

0.080

Polyphen

0.99

Vest4

0.56

MVP

0.80

MPC

0.73

ClinPred

0.097

GERP RS

3.7

Varity_R

0.33

gMVP

0.71

Mutation Taster

=82/18

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