chr16-84155744-G-A

Position:

chr16-84155744-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_178452.6(DNAAF1):c.736G>A(p.Asp246Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,614,010 control chromosomes in the GnomAD database, including 20 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 14 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.48

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=0.009695202).

BP6

Variant 16-84155744-G-A is Benign according to our data. Variant chr16-84155744-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00598 (910/152156) while in subpopulation AFR AF= 0.0202 (839/41496). AF 95% confidence interval is 0.0191. There are 6 homozygotes in gnomad4. There are 433 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6 linkuse as main transcript	c.736G>A	p.Asp246Asn	missense_variant	5/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10 linkuse as main transcript	c.736G>A	p.Asp246Asn	missense_variant	5/12	1	NM_178452.6	P1	Q8NEP3-1
DNAAF1	ENST00000567918.5 linkuse as main transcript	c.736G>A	p.Asp246Asn	missense_variant, NMD_transcript_variant	5/7	1
DNAAF1	ENST00000570298.5 linkuse as main transcript	n.890G>A		non_coding_transcript_exon_variant	5/11	2
DNAAF1	ENST00000563093.5 linkuse as main transcript	c.736G>A	p.Asp246Asn	missense_variant, NMD_transcript_variant	5/11	2			Q8NEP3-3

Frequencies

GnomAD3 genomes

AF:

0.00595

AC:

904

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0201

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00178

AC:

447

AN:

251418

Hom.:

AF XY:

0.00141

AC XY:

192

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0210

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000466

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00106

AC:

1554

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

722

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0210

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000587

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.00598

AC:

910

AN:

152156

Hom.:

Cov.:

AF XY:

0.00582

AC XY:

433

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0202

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.00689

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0175

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00222

AC:

270

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 23, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -

Primary ciliary dyskinesia 13

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.00071

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0097

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.6

REVEL

Benign

0.13

Sift

Benign

0.34

Sift4G

Benign

0.59

Polyphen

0.20

Vest4

0.35

MVP

0.31

MPC

0.020

ClinPred

0.0064

GERP RS

-2.0

Varity_R

0.064

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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