chr8-132572316-G-A

Variant names:

• chr8-132572316-G-A
• rs139131485
• NM_012472.6:c.1391C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_012472.6(DNAAF11):​c.1391C>T​(p.Pro464Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000873 in 1,612,294 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P464S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (10 hom.)
• Consequence: DNAAF11 NM_012472.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4 O:1
• Conservation: PhyloP100: 4.71
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 19

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011046588).
• BP6: Variant 8-132572316-G-A is Benign according to our data. Variant chr8-132572316-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260273.We mark this variant Benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000552 (84/152284) while in subpopulation SAS AF = 0.0054 (26/4818). AF 95% confidence interval is 0.00378. There are 1 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF11	NM_012472.6	c.1391C>T	p.Pro464Leu	missense_variant	Exon 12 of 12	ENST00000620350.5	NP_036604.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF11	ENST00000620350.5	c.1391C>T	p.Pro464Leu	missense_variant	Exon 12 of 12	1	NM_012472.6	ENSP00000484634.1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00137 AC: 341 AN: 249128 AF XY: 0.00181

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000675

Gnomad ASJ exome AF: 0.000502

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000708

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000906 AC: 1323 AN: 1460010 Hom.: 10 Cov.: 31 AF XY: 0.00118 AC XY: 858 AN XY: 726324

African (AFR) AF: 0.0000601 AC: 2 AN: 33284

American (AMR) AF: 0.000631 AC: 28 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.000461 AC: 12 AN: 26056

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.00845 AC: 726 AN: 85870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00452 AC: 26 AN: 5758

European-Non Finnish (NFE) AF: 0.000430 AC: 478 AN: 1111352

Other (OTH) AF: 0.000829 AC: 50 AN: 60298

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74462

African (AFR) AF: 0.0000241 AC: 1 AN: 41554

American (AMR) AF: 0.000915 AC: 14 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4818

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000575 Hom.: 2

Bravo AF: 0.000604

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00152 AC: 185

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 19 Uncertain:1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Uncertain:1

Jan 31, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The P464L variant in the LRRC6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, P464L was observed with an allele frequency of 0.72% in individuals of South Asian ancestry the Exome Aggregation Consortium (ExAC) data set, indicating it may be a rare variant in this population. The P464L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret P464L as a variant of uncertain significance. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia Benign:1

Oct 30, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Multiple sclerosis, susceptibility to Other:1

-

Department of Molecular Biology and Genetics, Acibadem University

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: research

A family with 4 affected and 4 unaffected members was analyzed. The variant is segregated with MS in a fully penetrant manner in the family. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T;.;T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.8	.;M;M;.
PhyloP100		4.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.8	.;.;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.64
MVP		0.68
ClinPred		0.16	T
GERP RS		5.7
Varity_R		0.52
gMVP		0.58
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs139131485; hg19: chr8-133584564; COSMIC: COSV51537371; COSMIC: COSV51537371;