rs112044935

chr14-49634422-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018139.3(DNAAF2):c.728A>C(p.Glu243Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,569,868 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E243K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0059 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (12 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.622

Genes affected

DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028954148).
• BP6: Variant 14-49634422-T-G is Benign according to our data. Variant chr14-49634422-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 261022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00588 (894/152098) while in subpopulation AFR AF= 0.0206 (856/41524). AF 95% confidence interval is 0.0195. There are 12 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF2	NM_018139.3	c.728A>C	p.Glu243Ala	missense_variant	1/3	ENST00000298292.13
DNAAF2	NM_001083908.2	c.728A>C	p.Glu243Ala	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13	c.728A>C	p.Glu243Ala	missense_variant	1/3	1	NM_018139.3	P2
DNAAF2	ENST00000406043.3	c.728A>C	p.Glu243Ala	missense_variant	1/2	1		A2

Frequencies

GnomAD3 genomes AF: 0.00585 AC: 889 AN: 151980 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00145 AC: 268 AN: 184552 Hom.: 3 AF XY: 0.00125 AC XY: 128 AN XY: 102742

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000877

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000604 AC: 857 AN: 1417770 Hom.: 12 Cov.: 88 AF XY: 0.000567 AC XY: 398 AN XY: 701406

Gnomad4 AFR exome AF: 0.0190

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000250

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000541

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00588 AC: 894 AN: 152098 Hom.: 12 Cov.: 33 AF XY: 0.00545 AC XY: 405 AN XY: 74366

Gnomad4 AFR AF: 0.0206

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00617

ESP6500AA AF: 0.0114 AC: 39

ESP6500EA AF: 0.000132 AC: 1

ExAC AF: 0.00138 AC: 161

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 08, 2015	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

-

- -

Primary ciliary dyskinesia 10 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	6.3
Dann	Benign	0.87
DEOGEN2	Benign	0.0054	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.027
Sift	Benign	0.31	T;T
Sift4G	Uncertain	0.041	D;D
Polyphen		0.0040	B;B
Vest4		0.14
MVP		0.21
MPC		0.83
ClinPred		0.013	T
GERP RS		-0.13
Varity_R		0.12
gMVP		0.42

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: rs112044935; hg19: chr14-50101140;