16-84170218-C-T

Position:

chr16-84170218-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_178452.6(DNAAF1):c.1390C>T(p.Pro464Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,000 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.403

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03618169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF1	NM_178452.6 linkuse as main transcript	c.1390C>T	p.Pro464Ser	missense_variant	8/12	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.1390C>T	p.Pro464Ser	missense_variant	8/12	1	NM_178452.6	ENSP00000367815	P1	Q8NEP3-1
DNAAF1	ENST00000563818.5 linkuse as main transcript	n.1067C>T		non_coding_transcript_exon_variant	4/8	2
DNAAF1	ENST00000570298.5 linkuse as main transcript	n.1544C>T		non_coding_transcript_exon_variant	8/11	2
DNAAF1	ENST00000563093.5 linkuse as main transcript	c.1226-24C>T		intron_variant, NMD_transcript_variant		2		ENSP00000457373		Q8NEP3-3

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

151082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251098

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460802

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000265

AC:

AN:

151198

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73918

show subpopulations

Gnomad4 AFR

AF:

0.0000488

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2021

This sequence change replaces proline with serine at codon 464 of the DNAAF1 protein (p.Pro464Ser). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs566279701, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with DNAAF1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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

Benign

0.087

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.9

DANN

Benign

0.40

DEOGEN2

Benign

0.0064

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.57

M_CAP

Benign

0.0031

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.26

REVEL

Benign

0.048

Sift

Benign

0.036

Sift4G

Benign

0.83

Polyphen

0.72

Vest4

0.16

MutPred

0.085

Gain of phosphorylation at P464 (P = 0.0178);

MVP

0.22

MPC

0.026

ClinPred

0.028

GERP RS

0.62

Varity_R

0.036

gMVP

0.098

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

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