rs149230619

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012144.4(DNAI1):c.476G>A(p.Ser159Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000812 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

DNAI1
NM_012144.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.66

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13966015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4 linkuse as main transcript	c.476G>A	p.Ser159Asn	missense_variant	6/20	ENST00000242317.9
DNAI1	NM_001281428.2 linkuse as main transcript	c.488G>A	p.Ser163Asn	missense_variant	6/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9 linkuse as main transcript	c.476G>A	p.Ser159Asn	missense_variant	6/20	1	NM_012144.4		Q9UI46-1
DNAI1	ENST00000614641.4 linkuse as main transcript	c.488G>A	p.Ser163Asn	missense_variant	6/20	5		P1
DNAI1	ENST00000437363.5 linkuse as main transcript	c.443G>A	p.Ser148Asn	missense_variant	5/9	5
DNAI1	ENST00000488369.1 linkuse as main transcript	n.592G>A		non_coding_transcript_exon_variant	6/9	3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251118

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135790

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:

0.0000969

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000869

AC:

127

AN:

1461778

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000965

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 05, 2022	The c.476G>A (p.S159N) alteration is located in exon 6 (coding exon 6) of the DNAI1 gene. This alteration results from a G to A substitution at nucleotide position 476, causing the serine (S) at amino acid position 159 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 24, 2022	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 159 of the DNAI1 protein (p.Ser159Asn). This variant is present in population databases (rs149230619, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 454837). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

Kartagener syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Dec 01, 2023

This DNAI1 missense variant (rs149230619) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 131/1613964 total alleles; 0.01%; no homozygotes). It has been reported in ClinVar (Variation ID 454837), but has not been reported in the literature, to our knowledge. Two bioinformatic tools queried predict that this substitution would be tolerated, and the serine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.476G>A in DNAI1 to be uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.37

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.011

T;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.55

T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.85

MutationTaster

Benign

0.91

PrimateAI

Benign

0.42

Sift4G

Benign

0.44

T;T;T

Polyphen

0.51

.;.;P

Vest4

0.36

MVP

0.81

MPC

0.11

ClinPred

0.16

GERP RS

3.7

Varity_R

0.049

gMVP

0.21

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