Genetic Variant DNAAF3:p.Arg214Ser (chr19-55161666-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001256715.2(DNAAF3):c.640C>A(p.Arg214Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,386,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R214C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DNAAF3
NM_001256715.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.03

Publications

0 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:

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

DNAAF3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0679338).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256715.2. 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.640C>A	p.Arg214Ser	missense	Exon 6 of 12	NP_001243644.1
DNAAF3	NM_001256714.1		c.844C>A	p.Arg282Ser	missense	Exon 6 of 12	NP_001243643.1
DNAAF3	NM_178837.4		c.781C>A	p.Arg261Ser	missense	Exon 6 of 12	NP_849159.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF3	ENST00000524407.7	TSL:1 MANE Select	c.640C>A	p.Arg214Ser	missense	Exon 6 of 12	ENSP00000432046.3
DNAAF3	ENST00000455045.5	TSL:1	c.478C>A	p.Arg160Ser	missense	Exon 6 of 12	ENSP00000394343.1
DNAAF3	ENST00000528412.5	TSL:1	n.*428C>A		non_coding_transcript_exon	Exon 6 of 12	ENSP00000433826.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1386558

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31456

American (AMR)

AF:

0.00

AC:

AN:

35586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25096

East Asian (EAS)

AF:

0.00

AC:

AN:

35660

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39644

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078276

Other (OTH)

AF:

0.00

AC:

AN:

57680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.046

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.00069

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.70

M_CAP

Benign

0.0092

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.47

PhyloP100

2.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.52

REVEL

Benign

0.20

Sift

Benign

0.95

Sift4G

Benign

0.76

Polyphen

0.031

Vest4

0.44

MutPred

0.34

Loss of MoRF binding (P = 0.0426)

MVP

0.14

MPC

1.7

ClinPred

0.22

GERP RS

3.2

Varity_R

0.16

gMVP

0.44

Mutation Taster

=93/7

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over