rs80237479

chr14-49625880-T-C

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.2176A>G(p.Thr726Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000981 in 1,613,344 control chromosomes in the GnomAD database, including 16 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T726T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (13 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0270

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=0.002492845).
• BP6: Variant 14-49625880-T-C is Benign according to our data. Variant chr14-49625880-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 241282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00112 (171/152362) while in subpopulation EAS AF= 0.0185 (96/5192). AF 95% confidence interval is 0.0155. There are 3 homozygotes in gnomad4. There are 121 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF2	NM_018139.3	c.2176A>G	p.Thr726Ala	missense_variant	3/3	ENST00000298292.13
DNAAF2	NM_001083908.2	c.2032A>G	p.Thr678Ala	missense_variant	2/2
DNAAF2	NM_001378453.1	c.-36A>G		5_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13	c.2176A>G	p.Thr726Ala	missense_variant	3/3	1	NM_018139.3	P2
DNAAF2	ENST00000406043.3	c.2032A>G	p.Thr678Ala	missense_variant	2/2	1		A2

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152242 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0186

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00233 AC: 583 AN: 250386 Hom.: 6 AF XY: 0.00222 AC XY: 301 AN XY: 135324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.0214

Gnomad SAS exome AF: 0.000921

Gnomad FIN exome AF: 0.00551

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.000966 AC: 1412 AN: 1460982 Hom.: 13 Cov.: 32 AF XY: 0.000966 AC XY: 702 AN XY: 726754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0211

Gnomad4 SAS exome AF: 0.000837

Gnomad4 FIN exome AF: 0.00598

Gnomad4 NFE exome AF: 0.0000927

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152362 Hom.: 3 Cov.: 33 AF XY: 0.00162 AC XY: 121 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0185

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00489

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00116 Hom.: 3

Bravo AF: 0.00117

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2021	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -

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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.3
Dann	Benign	0.73
DEOGEN2	Benign	0.0018	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.77	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.62	N;N
REVEL	Benign	0.042
Sift	Benign	1.0	T;T
Sift4G	Benign	0.88	T;T
Polyphen		0.0	B;B
Vest4		0.019
MVP		0.17
MPC		0.50
ClinPred		0.011	T
GERP RS		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.042

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: rs80237479; hg19: chr14-50092598; COSMIC: COSV53567956; COSMIC: COSV53567956;