rs9297853

Positions:

• chr8-132572310-A-G

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.1397T>C​(p.Ile466Thr) variant causes a missense change. The variant allele was found at a frequency of 0.1 in 1,611,468 control chromosomes in the GnomAD database, including 10,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2573 hom., cov: 32)
  • Exomes 𝑓: 0.095 (7997 hom.)
• Consequence: DNAAF11 NM_012472.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.93

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=0.0019569993).
• BP6: Variant 8-132572310-A-G is Benign according to our data. Variant chr8-132572310-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-132572310-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF11	NM_012472.6	c.1397T>C	p.Ile466Thr	missense_variant	12/12	ENST00000620350.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF11	ENST00000620350.5	c.1397T>C	p.Ile466Thr	missense_variant	12/12	1	NM_012472.6	P1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22926 AN: 152032 Hom.: 2568 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0558

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0924

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.0991 AC: 24690 AN: 249022 Hom.: 1789 AF XY: 0.0986 AC XY: 13275 AN XY: 134602

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.0542

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0459

Gnomad SAS exome AF: 0.110

Gnomad FIN exome AF: 0.0592

Gnomad NFE exome AF: 0.0939

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0952 AC: 138902 AN: 1459320 Hom.: 7997 Cov.: 31 AF XY: 0.0958 AC XY: 69526 AN XY: 725958

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.0601

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.0306

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0638

Gnomad4 NFE exome AF: 0.0910

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.151 AC: 22943 AN: 152148 Hom.: 2573 Cov.: 32 AF XY: 0.147 AC XY: 10924 AN XY: 74378

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.0876

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.0396

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.0558

Gnomad4 NFE AF: 0.0924

Gnomad4 OTH AF: 0.147

Alfa AF: 0.103 Hom.: 2527

Bravo AF: 0.160

TwinsUK AF: 0.0898 AC: 333

ALSPAC AF: 0.0947 AC: 365

ESP6500AA AF: 0.294 AC: 1297

ESP6500EA AF: 0.0967 AC: 832

ExAC AF: 0.105 AC: 12803

Asia WGS AF: 0.0850 AC: 301 AN: 3476

EpiCase AF: 0.0928

EpiControl AF: 0.0995

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 19 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	Uncertain	0.49
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;.;D
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.047	P;P;P
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.97	.;D;D;.
Vest4		0.14
ClinPred		0.027	T
GERP RS		5.7
Varity_R		0.15
gMVP		0.24

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: rs9297853; hg19: chr8-133584558; COSMIC: COSV51539954; COSMIC: COSV51539954;