rs144077436

Positions:

• chr14-49633566-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_018139.3(DNAAF2):​c.1584T>A​(p.Asn528Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,613,980 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (12 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.102

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008465558).
• BP6: Variant 14-49633566-A-T is Benign according to our data. Variant chr14-49633566-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193393.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000663 (101/152308) while in subpopulation SAS AF= 0.00497 (24/4828). AF 95% confidence interval is 0.00343. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF2	NM_018139.3	c.1584T>A	p.Asn528Lys	missense_variant	1/3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2	c.1584T>A	p.Asn528Lys	missense_variant	1/2		NP_001077377.1
DNAAF2	NM_001378453.1	c.-288T>A		5_prime_UTR_variant	1/2		NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13	c.1584T>A	p.Asn528Lys	missense_variant	1/3	1	NM_018139.3	ENSP00000298292	P2
DNAAF2	ENST00000406043.3	c.1584T>A	p.Asn528Lys	missense_variant	1/2	1		ENSP00000384862	A2

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00140 AC: 352 AN: 250904 Hom.: 2 AF XY: 0.00180 AC XY: 244 AN XY: 135676

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00647

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000856

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000931 AC: 1361 AN: 1461672 Hom.: 12 Cov.: 31 AF XY: 0.00115 AC XY: 839 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00314

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00660

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000535

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000765 AC XY: 57 AN XY: 74476

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000982 Hom.: 0

Bravo AF: 0.000502

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 15, 2018	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. -

Primary ciliary dyskinesia 10 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 05, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

DNAAF2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.084	T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.029
Sift	Benign	0.050	D;D
Sift4G	Benign	0.091	T;T
Polyphen		0.42	B;P
Vest4		0.084
MutPred		0.45		Gain of catalytic residue at P523 (P = 0);Gain of catalytic residue at P523 (P = 0);
MVP		0.15
MPC		0.65
ClinPred		0.047	T
GERP RS		0.18
Varity_R		0.15
gMVP		0.41

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: rs144077436; hg19: chr14-50100284; COSMIC: COSV53568456; COSMIC: COSV53568456;