16-84176132-T-C

Position:

chr16-84176132-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_178452.6(DNAAF1):c.1898T>C(p.Leu633Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,613,394 control chromosomes in the GnomAD database, including 100,022 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7327 hom., cov: 32)

Exomes 𝑓: 0.35 ( 92695 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.12

Variant links:

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DNAAF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.13282E-4).

BP6

Variant 16-84176132-T-C is Benign according to our data. Variant chr16-84176132-T-C is described in ClinVar as [Benign]. Clinvar id is 163087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84176132-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF1	NM_178452.6 linkuse as main transcript	c.1898T>C	p.Leu633Ser	missense_variant	11/12	ENST00000378553.10	NP_848547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10 linkuse as main transcript	c.1898T>C	p.Leu633Ser	missense_variant	11/12	1	NM_178452.6	ENSP00000367815	P1	Q8NEP3-1

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43702

AN:

151810

Hom.:

7313

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.389

Gnomad ASJ

AF:

0.304

Gnomad EAS

AF:

0.370

Gnomad SAS

AF:

0.272

Gnomad FIN

AF:

0.367

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.354

Gnomad OTH

AF:

0.293

GnomAD3 exomes

AF:

0.345

AC:

86355

AN:

250160

Hom.:

15926

AF XY:

0.343

AC XY:

46409

AN XY:

135324

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.472

Gnomad ASJ exome

AF:

0.294

Gnomad EAS exome

AF:

0.375

Gnomad SAS exome

AF:

0.270

Gnomad FIN exome

AF:

0.364

Gnomad NFE exome

AF:

0.358

Gnomad OTH exome

AF:

0.337

GnomAD4 exome

AF:

0.352

AC:

514435

AN:

1461466

Hom.:

92695

Cov.:

AF XY:

0.349

AC XY:

253665

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.0967

Gnomad4 AMR exome

AF:

0.464

Gnomad4 ASJ exome

AF:

0.297

Gnomad4 EAS exome

AF:

0.377

Gnomad4 SAS exome

AF:

0.269

Gnomad4 FIN exome

AF:

0.362

Gnomad4 NFE exome

AF:

0.363

Gnomad4 OTH exome

AF:

0.330

GnomAD4 genome

AF:

0.288

AC:

43724

AN:

151928

Hom.:

7327

Cov.:

AF XY:

0.292

AC XY:

21664

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.108

Gnomad4 AMR

AF:

0.390

Gnomad4 ASJ

AF:

0.304

Gnomad4 EAS

AF:

0.371

Gnomad4 SAS

AF:

0.272

Gnomad4 FIN

AF:

0.367

Gnomad4 NFE

AF:

0.354

Gnomad4 OTH

AF:

0.290

Alfa

AF:

0.338

Hom.:

22481

Bravo

AF:

0.287

TwinsUK

AF:

0.376

AC:

1394

ALSPAC

AF:

0.358

AC:

1379

ESP6500AA

AF:

0.111

AC:

489

ESP6500EA

AF:

0.355

AC:

3054

ExAC

AF:

0.336

AC:

40791

Asia WGS

AF:

0.282

AC:

981

AN:

3478

EpiCase

AF:

0.343

EpiControl

AF:

0.348

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu633Ser in exon 11 of DNAAF1: This variant is not expected to have clinical si gnificance because it has been identified in 35.5% (3054/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2288020). -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 13

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.010

DANN

Benign

0.37

DEOGEN2

Benign

0.0099

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.21

T;T

MetaRNN

Benign

0.00031

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.85

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.030

Sift

Benign

0.74

T;T

Sift4G

Benign

0.83

T;T

Polyphen

0.10

B;.

Vest4

0.034

MPC

0.022

ClinPred

0.0045

GERP RS

-3.4

Varity_R

0.023

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over