rs775335375

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_173494.2(DNAAF6):c.502C>T(p.Arg168Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000538 in 1,207,509 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000055 ( 0 hom. 23 hem. )

Consequence

DNAAF6
NM_173494.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.05

Publications

0 publications found

Variant links:

Genes affected

DNAAF6 (HGNC:28570): (dynein axonemal assembly factor 6) Enables dynein intermediate chain binding activity. Involved in flagellated sperm motility; inner dynein arm assembly; and outer dynein arm assembly. Located in trans-Golgi network. Implicated in primary ciliary dyskinesia 36. [provided by Alliance of Genome Resources, Apr 2022]

DNAAF6 Gene-Disease associations (from GenCC):

ciliary dyskinesia, primary, 36, X-linked
Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAAF6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32592106).

BS2

High AC in GnomAd4 at 5 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF6	NM_173494.2 link	c.502C>T	p.Arg168Cys	missense_variant	Exon 6 of 7	ENST00000372453.8	NP_775765.1
DNAAF6	NM_001169154.2 link	c.502C>T	p.Arg168Cys	missense_variant	Exon 7 of 8		NP_001162625.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DNAAF6	ENST00000372453.8 link	c.502C>T	p.Arg168Cys	missense_variant	Exon 6 of 7	1	NM_173494.2	ENSP00000361531.3
DNAAF6	ENST00000336387.4 link	c.502C>T	p.Arg168Cys	missense_variant	Exon 6 of 7	5		ENSP00000337757.4
DNAAF6	ENST00000535523.6 link	c.502C>T	p.Arg168Cys	missense_variant	Exon 7 of 8	5		ENSP00000441930.1
DNAAF6	ENST00000688816.1 link	c.405C>T	p.Phe135Phe	synonymous_variant	Exon 5 of 6			ENSP00000508655.1

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111537

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000168

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000501

AC:

AN:

179770

AF XY:

0.0000155

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1095972

Hom.:

Cov.:

AF XY:

0.0000636

AC XY:

AN XY:

361672

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26294

American (AMR)

AF:

0.00

AC:

AN:

34865

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19320

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30081

South Asian (SAS)

AF:

0.00

AC:

AN:

53596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40480

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.0000666

AC:

AN:

841218

Other (OTH)

AF:

0.0000435

AC:

AN:

46001

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000448

AC:

AN:

111537

Hom.:

Cov.:

AF XY:

0.0000593

AC XY:

AN XY:

33731

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30760

American (AMR)

AF:

0.00

AC:

AN:

10428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.000279

AC:

AN:

3588

South Asian (SAS)

AF:

0.00

AC:

AN:

2660

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

5968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000565

AC:

AN:

53063

Other (OTH)

AF:

0.00

AC:

AN:

1500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000868

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000110

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ciliary dyskinesia, primary, 36, X-linked

Uncertain:1

Jul 10, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the PIH1D3 protein (p.Arg168Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PIH1D3-related conditions. ClinVar contains an entry for this variant (Variation ID: 562215). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

T;T;T

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.82

T;.;.

M_CAP

Benign

0.022

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.2

M;M;M

PhyloP100

2.0

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.3

D;D;D

REVEL

Benign

0.14

Sift

Benign

0.039

D;D;D

Sift4G

Benign

0.082

T;T;T

Polyphen

0.94

P;P;P

Vest4

0.51

MVP

0.28

MPC

0.28

ClinPred

0.73

GERP RS

3.7

Varity_R

0.35

gMVP

0.78

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over