chr14-49633733-G-A

Position:

chr14-49633733-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018139.3(DNAAF2):c.1417C>T(p.Arg473Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000759 in 1,594,842 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00079 ( 4 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.480

Variant links:

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]

DNAAF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070435107).

BP6

Variant 14-49633733-G-A is Benign according to our data. Variant chr14-49633733-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216703.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000486 (74/152274) while in subpopulation SAS AF= 0.00145 (7/4826). AF 95% confidence interval is 0.000716. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNAAF2	NM_018139.3 linkuse as main transcript	c.1417C>T	p.Arg473Trp	missense_variant	1/3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2 linkuse as main transcript	c.1417C>T	p.Arg473Trp	missense_variant	1/2		NP_001077377.1
DNAAF2	NM_001378453.1 linkuse as main transcript	c.-455C>T		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 linkuse as main transcript	c.1417C>T	p.Arg473Trp	missense_variant	1/3	1	NM_018139.3	ENSP00000298292	P2	Q9NVR5-1
DNAAF2	ENST00000406043.3 linkuse as main transcript	c.1417C>T	p.Arg473Trp	missense_variant	1/2	1		ENSP00000384862	A2	Q9NVR5-2

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000505

AC:

119

AN:

235636

Hom.:

AF XY:

0.000552

AC XY:

AN XY:

128574

show subpopulations

Gnomad AFR exome

AF:

0.000264

Gnomad AMR exome

AF:

0.0000910

Gnomad ASJ exome

AF:

0.000113

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00177

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000546

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.000787

AC:

1136

AN:

1442568

Hom.:

Cov.:

AF XY:

0.000812

AC XY:

581

AN XY:

715828

show subpopulations

Gnomad4 AFR exome

AF:

0.000273

Gnomad4 AMR exome

AF:

0.0000695

Gnomad4 ASJ exome

AF:

0.0000793

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00170

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000855

Gnomad4 OTH exome

AF:

0.000571

GnomAD4 genome

AF:

0.000486

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000366

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000237

AC:

ESP6500EA

AF:

0.00130

AC:

ExAC

AF:

0.000504

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 13, 2022	This alteration is classified as likely 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 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, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0081

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0086

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.022

Sift

Uncertain

0.023

D;D

Sift4G

Uncertain

0.030

D;D

Polyphen

0.0

B;B

Vest4

0.10

MVP

0.20

MPC

0.72

ClinPred

0.069

GERP RS

-4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.044

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over