rs368248592

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_012144.4(DNAI1):c.1612G>A(p.Ala538Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A538S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

DNAI1
NM_012144.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.12

Variant links:

Genes affected

DNAI1 (HGNC:2954): (dynein axonemal intermediate chain 1) This gene encodes a member of the dynein intermediate chain family. The encoded protein is part of the dynein complex in respiratory cilia. The inner- and outer-arm dyneins, which bridge between the doublet microtubules in axonemes, are the force-generating proteins responsible for the sliding movement in axonemes. The intermediate and light chains, thought to form the base of the dynein arm, help mediate attachment and may also participate in regulating dynein activity. Mutations in this gene result in abnormal ciliary ultrastructure and function associated with primary ciliary dyskinesia and Kartagener syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

DNAI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a repeat WD 5 (size 39) in uniprot entity DNAI1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_012144.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-34514437-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1481187.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 9-34514436-G-A is Pathogenic according to our data. Variant chr9-34514436-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 583106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4 linkuse as main transcript	c.1612G>A	p.Ala538Thr	missense_variant	17/20	ENST00000242317.9
DNAI1	NM_001281428.2 linkuse as main transcript	c.1624G>A	p.Ala542Thr	missense_variant	17/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9 linkuse as main transcript	c.1612G>A	p.Ala538Thr	missense_variant	17/20	1	NM_012144.4		Q9UI46-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251310

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000930

AC:

136

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000112

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 10, 2015	The p.A538T pathogenic mutation (also known as c.1612G>A), located in coding exon 17 of the DNAI1 gene, results from a G to A substitution at nucleotide position 1612. The alanine at codon 538 is replaced by threonine, an amino acid with some similar properties. This alteration was first reported in two unrelated individuals with symptoms of PCD with a second pathogenic alteration (confirmed in trans in one patient); both patients had outer dynein arm defects identified by ultrastructual analysis (Zariwala MA et al. Am J Respir Crit Care Med. 2006;174(8):858-66). In addition, this alteration was identified in the homozygous state in three families and in conjunction with another pathogenic mutation in an additional two patients, all who had symptoms of PCD and dynein arm defects; authors suggest this alteration may be a Polish founder mutation (Zitkiewicz E et al. Respir Res. 2010;11:174). Based on the supporting evidence, p.A538T is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 538 of the DNAI1 protein (p.Ala538Thr). This variant is present in population databases (rs368248592, gnomAD 0.01%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16858015, 21143860). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 583106). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNAI1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Aug 01, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Jul 07, 2022

ACMG categories: PS4,PM1,PM2,PM3,PP1,PP3,PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.11

T;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

-0.081

MutationAssessor

Uncertain

2.4

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.2

.;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0040

.;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.98

.;D

Vest4

0.93

MutPred

0.82

.;Loss of catalytic residue at A538 (P = 0.1088);

MVP

0.87

MPC

0.53

ClinPred

0.68

GERP RS

5.5

Varity_R

0.71

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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