9-34497160-C-T

Position:

chr9-34497160-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_012144.4(DNAI1):c.862C>T(p.Arg288Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000915 in 1,614,022 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 20 hom. )

Consequence

DNAI1
NM_012144.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:5

Conservation

PhyloP100: 6.86

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 -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.0115557015).

BP6

Variant 9-34497160-C-T is Benign according to our data. Variant chr9-34497160-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 220955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000598 (91/152250) while in subpopulation SAS AF= 0.0174 (84/4820). AF 95% confidence interval is 0.0144. There are 0 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI1	NM_012144.4 link	c.862C>T	p.Arg288Trp	missense_variant	10/20	ENST00000242317.9	NP_036276.1	Q9UI46-1A0A140VJI0
DNAI1	NM_001281428.2 link	c.874C>T	p.Arg292Trp	missense_variant	10/20		NP_001268357.1	Q9UI46A0A087WWV9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAI1	ENST00000242317.9 link	c.862C>T	p.Arg288Trp	missense_variant	10/20	1	NM_012144.4	ENSP00000242317.4	Q9UI46-1
DNAI1	ENST00000614641.4 link	c.874C>T	p.Arg292Trp	missense_variant	10/20	5		ENSP00000480538.1	A0A087WWV9
DNAI1	ENST00000437363.5 link	c.829C>T	p.Arg277Trp	missense_variant	9/9	5		ENSP00000395396.1	Q5T8G8

Frequencies

GnomAD3 genomes

AF:

0.000598

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00177

AC:

444

AN:

251456

Hom.:

AF XY:

0.00245

AC XY:

333

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0140

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000948

AC:

1386

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

999

AN XY:

727192

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:

0.0142

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.000598

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000927

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000989

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.00196

AC:

238

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2019	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 16, 2020	- -

Kartagener syndrome

Pathogenic:1Benign:1

Likely pathogenic, flagged submission	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	May 28, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

DNAI1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;T;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.5

.;.;H

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.2

.;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.93

MutPred

0.55

.;.;Loss of disorder (P = 0.0135);

MVP

0.98

MPC

0.56

ClinPred

0.23

GERP RS

6.0

Varity_R

0.79

gMVP

0.84

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