14-49625416-A-T

Position:

• chr14-49625416-A-T

Variant summary

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

The NM_018139.3(DNAAF2):​c.*126T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 725,522 control chromosomes in the GnomAD database, including 16,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6696 hom., cov: 32)
  • Exomes 𝑓: 0.18 (10229 hom.)
• Consequence: DNAAF2 NM_018139.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.92

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 (BayesDel_noAF=-0.92).
• BP6: Variant 14-49625416-A-T is Benign according to our data. Variant chr14-49625416-A-T is described in ClinVar as [Benign]. Clinvar id is 313274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF2	NM_018139.3	c.*126T>A		3_prime_UTR_variant	3/3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2	c.*126T>A		3_prime_UTR_variant	2/2		NP_001077377.1
DNAAF2	NM_001378453.1	c.*126T>A		3_prime_UTR_variant	2/2		NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292	c.*126T>A		3_prime_UTR_variant	3/3	1	NM_018139.3	ENSP00000298292.8
DNAAF2	ENST00000406043	c.*126T>A		3_prime_UTR_variant	2/2	1		ENSP00000384862.3

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38925 AN: 151672 Hom.: 6684 Cov.: 32

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.179 AC: 102798 AN: 573736 Hom.: 10229 Cov.: 8 AF XY: 0.178 AC XY: 49917 AN XY: 280854

Gnomad4 AFR exome AF: 0.505

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.241

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.257 AC: 38976 AN: 151786 Hom.: 6696 Cov.: 32 AF XY: 0.254 AC XY: 18848 AN XY: 74224

Gnomad4 AFR AF: 0.489

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.205

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.229

Alfa AF: 0.217 Hom.: 575

Bravo AF: 0.271

Asia WGS AF: 0.221 AC: 771 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 10 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.38
DANN	Benign	0.046

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: rs8952; hg19: chr14-50092134; COSMIC: COSV53565804; COSMIC: COSV53565804;