Genetic Variant NM_012472.6:c.1343T>C (chr8-132572364-A-G) – 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_012472.6(DNAAF11):c.1343T>C(p.Ile448Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,042 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0015 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 22 hom. )

Consequence

DNAAF11
NM_012472.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.17

Publications

4 publications found

Variant links:

Genes affected

DNAAF11 (HGNC:16725): (dynein axonemal assembly factor 11) The protein encoded by this gene contains several leucine-rich repeat domains and appears to be involved in the motility of cilia. Defects in this gene are a cause of primary ciliary dyskinesia-19 (CILD19). Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 4, 11 and 22. [provided by RefSeq, Apr 2016]

DNAAF11 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 19
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen

DNAAF11 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=0.0027182996).

BP6

Variant 8-132572364-A-G is Benign according to our data. Variant chr8-132572364-A-G is described in ClinVar as Benign. ClinVar VariationId is 260272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00149 (227/152272) while in subpopulation EAS AF = 0.0389 (201/5166). AF 95% confidence interval is 0.0345. There are 5 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012472.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF11	NM_012472.6	MANE Select	c.1343T>C	p.Ile448Thr	missense	Exon 12 of 12	NP_036604.2
DNAAF11	NM_001321961.2		c.1283T>C	p.Ile428Thr	missense	Exon 11 of 11	NP_001308890.1
DNAAF11	NM_001321962.2		c.1097T>C	p.Ile366Thr	missense	Exon 10 of 10	NP_001308891.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF11	ENST00000620350.5	TSL:1 MANE Select	c.1343T>C	p.Ile448Thr	missense	Exon 12 of 12	ENSP00000484634.1
DNAAF11	ENST00000519595.5	TSL:1	c.1343T>C	p.Ile448Thr	missense	Exon 12 of 12	ENSP00000429791.1
DNAAF11	ENST00000250173.5	TSL:1	c.*207T>C		3_prime_UTR	Exon 13 of 13	ENSP00000250173.2

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

228

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0390

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00340

AC:

854

AN:

251300

AF XY:

0.00308

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0453

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000989

AC:

1446

AN:

1461770

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

703

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33470

American (AMR)

AF:

0.000134

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0329

AC:

1306

AN:

39696

South Asian (SAS)

AF:

0.000267

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111940

Other (OTH)

AF:

0.00126

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

169

254

338

423

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00149

AC:

227

AN:

152272

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41568

American (AMR)

AF:

0.000458

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0389

AC:

201

AN:

5166

South Asian (SAS)

AF:

0.00124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00139

Hom.:

Bravo

AF:

0.00201

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.00331

AC:

402

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia 19 (2)

not provided (1)

not specified (1)

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.0050

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.0027

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

-1.2

PrimateAI

Benign

0.30

PROVEAN

Benign

0.95

REVEL

Benign

0.0030

Sift

Benign

0.57

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.043

MVP

0.055

ClinPred

0.00030

GERP RS

-2.5

Varity_R

0.020

gMVP

0.088

Mutation Taster

=99/1

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