19-55161087-G-A

Position:

chr19-55161087-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001256715.2(DNAAF3):c.890C>T(p.Thr297Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,542,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 0 hom. )

Consequence

DNAAF3
NM_001256715.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.12

Variant links:

Genes affected

DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

DNAAF3 links:

DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

DNAAF3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20843536).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000423 (588/1390414) while in subpopulation NFE AF= 0.000538 (580/1078244). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4_exome. There are 281 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF3	NM_001256715.2 linkuse as main transcript	c.890C>T	p.Thr297Met	missense_variant	8/12	ENST00000524407.7	NP_001243644.1
DNAAF3-AS1	XR_007067344.1 linkuse as main transcript	n.179G>A		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7 linkuse as main transcript	c.890C>T	p.Thr297Met	missense_variant	8/12	1	NM_001256715.2	ENSP00000432046	A2	Q8N9W5-1
DNAAF3-AS1	ENST00000591665.1 linkuse as main transcript	n.1009G>A		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes

AF:

0.000119

AC:

AN:

151856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000145

AC:

AN:

144756

Hom.:

AF XY:

0.000141

AC XY:

AN XY:

78084

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000373

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000423

AC:

588

AN:

1390414

Hom.:

Cov.:

AF XY:

0.000410

AC XY:

281

AN XY:

686026

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000538

Gnomad4 OTH exome

AF:

0.0000866

GnomAD4 genome

AF:

0.000119

AC:

AN:

151856

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74138

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000381

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000684

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 365 of the DNAAF3 protein (p.Thr365Met). This variant is present in population databases (rs549181425, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DNAAF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 330214). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 16, 2023	The c.1094C>T (p.T365M) alteration is located in exon 8 (coding exon 8) of the DNAAF3 gene. This alteration results from a C to T substitution at nucleotide position 1094, causing the threonine (T) at amino acid position 365 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

.;T;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.8

.;M;.;.

MutationTaster

Benign

0.93

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.6

D;.;.;D

REVEL

Benign

0.17

Sift

Uncertain

0.013

D;.;.;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.25

MVP

0.42

MPC

0.86

ClinPred

0.60

GERP RS

4.2

Varity_R

0.13

gMVP

0.79

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