8-132632819-G-C

Position:

chr8-132632819-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_012472.6(DNAAF11):c.574C>G(p.Gln192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,834 control chromosomes in the GnomAD database, including 5 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 5 hom. )

Consequence

DNAAF11
NM_012472.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 1.32

Variant links:

Genes affected

DNAAF11 (HGNC:16725): (dynein axonemal assembly factor 11) The protein encoded by this gene contains several leucine-rich repeat domains and appears to be involved in the motility of cilia. Defects in this gene are a cause of primary ciliary dyskinesia-19 (CILD19). Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 4, 11 and 22. [provided by RefSeq, Apr 2016]

DNAAF11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005859345).

BP6

Variant 8-132632819-G-C is Benign according to our data. Variant chr8-132632819-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540332.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0012 (182/152166) while in subpopulation NFE AF= 0.00209 (142/68018). AF 95% confidence interval is 0.00181. There are 0 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF11	NM_012472.6 link	c.574C>G	p.Gln192Glu	missense_variant	5/12	ENST00000620350.5	NP_036604.2	Q86X45-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF11	ENST00000620350.5 link	c.574C>G	p.Gln192Glu	missense_variant	5/12	1	NM_012472.6	ENSP00000484634.1		Q86X45-1

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

182

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000850

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00209

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00148

AC:

373

AN:

251390

Hom.:

AF XY:

0.00151

AC XY:

205

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00272

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00182

AC:

2661

AN:

1461668

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1293

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00101

Gnomad4 NFE exome

AF:

0.00222

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.00120

AC:

182

AN:

152166

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000850

Gnomad4 NFE

AF:

0.00209

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00184

Hom.:

Bravo

AF:

0.00129

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00159

AC:

193

EpiCase

AF:

0.00234

EpiControl

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 19

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 13, 2020	- -
Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 25, 2022	The DNAAF11 c.574C>G; p.Gln192Glu variant (rs141945265), to our knowledge, is not reported in the medical literature; but is reported in ClinVar (Variation ID: 540332). This variant is found in the general population with an overall allele frequency of 0.15% (427/282786 alleles) in the Genome Aggregation Database. The glutamine at codon 192 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.104). Due to limited information, the clinical significance of the this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 26, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

DNAAF11-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2023

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). -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

2.1

DANN

Benign

0.19

DEOGEN2

Benign

0.0026

.;T;T;T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.60

T;T;.;.;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0059

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

.;N;N;.;.

PrimateAI

Benign

0.19

PROVEAN

Benign

-0.15

.;.;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.67

.;.;T;T;T

Sift4G

Benign

0.80

T;T;T;T;T

Polyphen

0.0

.;B;B;.;.

Vest4

0.078

MVP

0.15

MPC

0.074

ClinPred

0.0025

GERP RS

2.4

Varity_R

0.066

gMVP

0.13

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