rs76334696

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_012144.4(DNAI1):c.1604C>A(p.Thr535Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,614,238 control chromosomes in the GnomAD database, including 278 homozygotes. In-silico tool predicts 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. T535A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0076 ( 29 hom., cov: 32)

Exomes 𝑓: 0.0064 ( 249 hom. )

Consequence

DNAI1
NM_012144.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.67

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 Benign. 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0071043074).

BP6

Variant 9-34514428-C-A is Benign according to our data. Variant chr9-34514428-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 178763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4 linkuse as main transcript	c.1604C>A	p.Thr535Asn	missense_variant	17/20	ENST00000242317.9
DNAI1	NM_001281428.2 linkuse as main transcript	c.1616C>A	p.Thr539Asn	missense_variant	17/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9 linkuse as main transcript	c.1604C>A	p.Thr535Asn	missense_variant	17/20	1	NM_012144.4		Q9UI46-1

Frequencies

GnomAD3 genomes

AF:

0.00763

AC:

1162

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0643

Gnomad SAS

AF:

0.0480

Gnomad FIN

AF:

0.0432

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00134

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.0154

AC:

3861

AN:

251334

Hom.:

102

AF XY:

0.0168

AC XY:

2277

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.0680

Gnomad SAS exome

AF:

0.0470

Gnomad FIN exome

AF:

0.0428

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.00643

AC:

9395

AN:

1461882

Hom.:

249

Cov.:

AF XY:

0.00771

AC XY:

5605

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.0598

Gnomad4 SAS exome

AF:

0.0453

Gnomad4 FIN exome

AF:

0.0416

Gnomad4 NFE exome

AF:

0.000333

Gnomad4 OTH exome

AF:

0.00782

GnomAD4 genome

AF:

0.00761

AC:

1160

AN:

152356

Hom.:

Cov.:

AF XY:

0.00985

AC XY:

734

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000980

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0642

Gnomad4 SAS

AF:

0.0480

Gnomad4 FIN

AF:

0.0432

Gnomad4 NFE

AF:

0.00134

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00327

Hom.:

Bravo

AF:

0.00343

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0152

AC:

1845

Asia WGS

AF:

0.0450

AC:

158

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 02, 2015	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr535Asn in exon 17 of DNAI1: This variant is not expected to have clinical sig nificance because it has been identified in 5.9% (11/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.go v/projects/SNP; dbSNP rs76334696). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

0.079

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.92

D;D

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.2

.;M

MutationTaster

Benign

0.73

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.0

.;D

REVEL

Benign

0.18

Sift

Uncertain

0.0040

.;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.0090

.;B

Vest4

0.18

MPC

0.20

ClinPred

0.029

GERP RS

4.6

Varity_R

0.46

gMVP

0.48

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