rs149980915

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_017802.4(DNAAF5):c.640C>G(p.Gln214Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,614,100 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. Q214H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00059 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

DNAAF5
NM_017802.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.30

Variant links:

Genes affected

DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

DNAAF5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010944217).

BP6

Variant 7-729707-C-G is Benign according to our data. Variant chr7-729707-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 525483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000591 (90/152336) while in subpopulation NFE AF= 0.000706 (48/68030). AF 95% confidence interval is 0.000547. There are 1 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DNAAF5	NM_017802.4 linkuse as main transcript	c.640C>G	p.Gln214Glu	missense_variant	2/13	ENST00000297440.11
DNAAF5	XM_024446813.2 linkuse as main transcript	c.640C>G	p.Gln214Glu	missense_variant	2/12
DNAAF5	NR_075098.2 linkuse as main transcript	n.618-18C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11 linkuse as main transcript	c.640C>G	p.Gln214Glu	missense_variant	2/13	1	NM_017802.4	P1	Q86Y56-1
DNAAF5	ENST00000437419.5 linkuse as main transcript	c.97+2392C>G		intron_variant		5
DNAAF5	ENST00000440747.5 linkuse as main transcript	c.62-18C>G		intron_variant		2
DNAAF5	ENST00000438961.1 linkuse as main transcript	n.109C>G		non_coding_transcript_exon_variant	2/5	4

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000705

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000642

AC:

161

AN:

250846

Hom.:

AF XY:

0.000655

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00378

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.000662

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000500

AC:

731

AN:

1461764

Hom.:

Cov.:

AF XY:

0.000536

AC XY:

390

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00314

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00105

Gnomad4 NFE exome

AF:

0.000458

Gnomad4 OTH exome

AF:

0.000844

GnomAD4 genome

AF:

0.000591

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000934

Hom.:

Bravo

AF:

0.000461

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000601

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 09, 2017	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 18

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 09, 2023

- -

DNAAF5-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0051

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.5

REVEL

Benign

0.086

Sift

Benign

0.36

Sift4G

Uncertain

0.026

Polyphen

0.70

Vest4

0.51

MVP

0.048

MPC

0.23

ClinPred

0.034

GERP RS

5.1

Varity_R

0.18

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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