chr16-84154585-C-T

Position:

chr16-84154585-C-T

Variant summary

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

The NM_178452.6(DNAAF1):c.361C>T(p.Arg121Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,613,930 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 4 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.552

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:

DNAAF1 (HGNC:):

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=0.008552581).

BP6

Variant 16-84154585-C-T is Benign according to our data. Variant chr16-84154585-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 701164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00025 (38/152216) while in subpopulation SAS AF= 0.0056 (27/4822). AF 95% confidence interval is 0.00395. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF1	NM_178452.6 linkuse as main transcript	c.361C>T	p.Arg121Cys	missense_variant	4/12	ENST00000378553.10	NP_848547.4	Q8NEP3-1A0A140VJN4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAAF1	ENST00000378553.10 linkuse as main transcript	c.361C>T	p.Arg121Cys	missense_variant	4/12	1	NM_178452.6	ENSP00000367815.5	Q8NEP3-1
DNAAF1	ENST00000567918.5 linkuse as main transcript	n.361C>T		non_coding_transcript_exon_variant	4/7	1		ENSP00000455154.1	H3BP51
DNAAF1	ENST00000563093.5 linkuse as main transcript	n.361C>T		non_coding_transcript_exon_variant	4/11	2		ENSP00000457373.1	Q8NEP3-3
DNAAF1	ENST00000570298.5 linkuse as main transcript	n.515C>T		non_coding_transcript_exon_variant	4/11	2

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000839

AC:

211

AN:

251400

Hom.:

AF XY:

0.00110

AC XY:

150

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00624

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000351

AC:

513

AN:

1461714

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

371

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00515

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.000250

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00560

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.000147

ExAC

AF:

0.000939

AC:

114

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 21, 2022	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. -

Primary ciliary dyskinesia 13

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

DNAAF1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.021

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.0090

MetaRNN

Benign

0.0086

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.015

Sift

Benign

0.19

Sift4G

Benign

0.098

Polyphen

0.12

Vest4

0.30

MutPred

0.45

Gain of ubiquitination at K117 (P = 0.0978);

MVP

0.26

MPC

0.023

ClinPred

0.016

GERP RS

1.9

Varity_R

0.10

gMVP

0.52

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