rs2293979

chr8-132625413-G-Achr8-132625413-G-Cchr8-132625413-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012472.6(DNAAF11):c.695C>T(p.Thr232Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,610,902 control chromosomes in the GnomAD database, including 152,357 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (22834 hom., cov: 32)
  • Exomes 𝑓: 0.41 (129523 hom.)
• Consequence: DNAAF11 NM_012472.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.93

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.4263197E-7).
• BP6: Variant 8-132625413-G-A is Benign according to our data. Variant chr8-132625413-G-A is described in ClinVar as [Benign]. Clinvar id is 260278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132625413-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF11	NM_012472.6	c.695C>T	p.Thr232Ile	missense_variant	6/12	ENST00000620350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF11	ENST00000620350.5	c.695C>T	p.Thr232Ile	missense_variant	6/12	1	NM_012472.6	P1

Frequencies

GnomAD3 genomes AF: 0.507 AC: 77019 AN: 151880 Hom.: 22781 Cov.: 32

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.482

GnomAD3 exomes AF: 0.401 AC: 100198 AN: 249622 Hom.: 22499 AF XY: 0.402 AC XY: 54221 AN XY: 134884

Gnomad AFR exome AF: 0.840

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.297

Gnomad SAS exome AF: 0.419

Gnomad FIN exome AF: 0.337

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.405

GnomAD4 exome AF: 0.412 AC: 601037 AN: 1458904 Hom.: 129523 Cov.: 35 AF XY: 0.412 AC XY: 298992 AN XY: 725784

Gnomad4 AFR exome AF: 0.840

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.373

Gnomad4 EAS exome AF: 0.228

Gnomad4 SAS exome AF: 0.420

Gnomad4 FIN exome AF: 0.345

Gnomad4 NFE exome AF: 0.415

Gnomad4 OTH exome AF: 0.425

GnomAD4 genome AF: 0.507 AC: 77133 AN: 151998 Hom.: 22834 Cov.: 32 AF XY: 0.499 AC XY: 37029 AN XY: 74266

Gnomad4 AFR AF: 0.830

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.375

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.417

Gnomad4 FIN AF: 0.334

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.489

Alfa AF: 0.421 Hom.: 36471

Bravo AF: 0.517

TwinsUK AF: 0.405 AC: 1501

ALSPAC AF: 0.413 AC: 1590

ESP6500AA AF: 0.818 AC: 3606

ESP6500EA AF: 0.425 AC: 3654

ExAC AF: 0.418 AC: 50696

Asia WGS AF: 0.383 AC: 1335 AN: 3478

EpiCase AF: 0.408

EpiControl AF: 0.408

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 19 Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2016	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.0040
Dann	Benign	0.53
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.17	T;T;.;.;T
MetaRNN	Benign	9.4e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.0	.;B;B;.;.
Vest4		0.013
MPC		0.073
ClinPred		0.015	T
GERP RS		-9.6
Varity_R		0.022
gMVP		0.16

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

Other links and lift over

dbSNP: rs2293979; hg19: chr8-133637659; COSMIC: COSV51539603; COSMIC: COSV51539603;