chr9-34513112-G-A

Position:

chr9-34513112-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5

The ENST00000242317.9(DNAI1):c.1490G>A(p.Gly497Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G497S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

DNAI1
ENST00000242317.9 missense, splice_region

Scores

Splicing: ADA: 0.9995

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 3.28

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-34513112-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1067969.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.799

PP5

Variant 9-34513112-G-A is Pathogenic according to our data. Variant chr9-34513112-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65703.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI1	NM_012144.4 linkuse as main transcript	c.1490G>A	p.Gly497Asp	missense_variant, splice_region_variant	16/20	ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2 linkuse as main transcript	c.1502G>A	p.Gly501Asp	missense_variant, splice_region_variant	16/20		NP_001268357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI1	ENST00000242317.9 linkuse as main transcript	c.1490G>A	p.Gly497Asp	missense_variant, splice_region_variant	16/20	1	NM_012144.4	ENSP00000242317		Q9UI46-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251480

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000759

AC:

111

AN:

1461662

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000720

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000761

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Kartagener syndrome

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 11, 2018	The DNAI1 c.1490G>A (p.Gly497Asp) variant is a missense variant that has been reported in a compound heterozygous state with a second common splice variant in one individual with primary ciliary dyskinesia (Zariwala et al. 2006). Family studies revealed that the individuals healthy father was heterozygous for the p.Gly497Asp variant, while the healthy mother was heterozygous for the splice variant. Fedick et al. (2015) also identified the p.Gly497Asp variant in a heterozygous state in three healthy Ashkenazi Jewish individuals. The p.Gly497Asp variant was absent from 211 control subjects but is reported at a frequency of 0.001117 in the Ashkenazi Jewish population of the Genome Aggregation Database. RT-PCR showed that this variant affected splicing, leading to in-frame deletion of exons 15 and 16 (Zariwala et al. 2006). Based on the limited evidence, the p.Gly497Asp variant is classified as a variant of uncertain significance but suspicious for pathogenicity for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 22, 2018	- -

Primary ciliary dyskinesia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 26, 2016	The p.G497D pathogenic mutation (also known as c.1490G>A) is located in coding exon 16 of the DNAI1 gene. The glycine at codon 497 is replaced by aspartic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 16. This mutation was detected in a patient with primary ciliary dyskinesia who was compound heterozygous for another DNAI mutation. The two mutations were confirmed through family studies to be in trans. Parental RNA analysis revealed an aberrant splice product from the p.G497D allele, leading to an in-frame deletion of 56 amino acids due to skipping of exons 15 and 16 (Zariwala MA, Am. J. Respir. Crit. Care Med. 2006 Oct; 174(8):858-66). Based on the supporting evidence, p.G497D is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 497 of the DNAI1 protein (p.Gly497Asp). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs376252276, gnomAD 0.1%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16858015). 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: 65703). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Studies have shown that this missense change results in skipping of exons 15-16, but is expected to preserve the integrity of the reading-frame (PMID: 16858015). For these reasons, this variant has been classified as Pathogenic. -

DNAI1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2023

The DNAI1 c.1490G>A variant is predicted to result in the amino acid substitution p.Gly497Asp. This variant was reported in the compound heterozygous state, along with the pathogenic c.48+2dup variant, in an individual with primary ciliary dyskinesia (Zariwala et al. 2006. PubMed ID: 16858015). mRNA studies showed that this variant causes the skipping of exons 15 and 16 and results in an in-frame deletion of 56 amino acids (R468_K523del) (Zariwala et al. 2006. PubMed ID: 16858015). This variant is reported in 0.13% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-34513110-G-A). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.022

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.3

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.6

.;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0030

.;D

Sift4G

Benign

0.073

T;T

Polyphen

0.12

.;B

Vest4

0.95

MVP

0.95

MPC

0.20

ClinPred

0.55

GERP RS

6.0

Varity_R

0.66

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.21

Position offset: 0

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