chr9-34459045-C-T

Position:

chr9-34459045-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_012144.4(DNAI1):c.40C>T(p.His14Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,046 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 2 hom. )

Consequence

DNAI1
NM_012144.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.90

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:

DNAI1 (HGNC:):

DNAI1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017238647).

BP6

Variant 9-34459045-C-T is Benign according to our data. Variant chr9-34459045-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 580210.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI1	NM_012144.4 linkuse as main transcript	c.40C>T	p.His14Tyr	missense_variant	1/20	ENST00000242317.9	NP_036276.1	Q9UI46-1A0A140VJI0
DNAI1	NM_001281428.2 linkuse as main transcript	c.40C>T	p.His14Tyr	missense_variant	1/20		NP_001268357.1	Q9UI46A0A087WWV9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAI1	ENST00000242317.9 linkuse as main transcript	c.40C>T	p.His14Tyr	missense_variant	1/20	1	NM_012144.4	ENSP00000242317.4	Q9UI46-1
DNAI1	ENST00000614641.4 linkuse as main transcript	c.40C>T	p.His14Tyr	missense_variant	1/20	5		ENSP00000480538.1	A0A087WWV9
DNAI1	ENST00000437363.5 linkuse as main transcript	c.40C>T	p.His14Tyr	missense_variant	1/9	5		ENSP00000395396.1	Q5T8G8
DNAI1	ENST00000470982.5 linkuse as main transcript	n.47+1585C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251374

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.000145

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.000157

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:

0.00

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000532

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00183

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

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:

0.000135

Hom.:

Bravo

AF:

0.000631

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 22, 2018	The p.H14Y variant (also known as c.40C>T), located in coding exon 1 of the DNAI1 gene, results from a C to T substitution at nucleotide position 40. The histidine at codon 14 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.010

T;T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.36

T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.0

.;.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.69

.;N;N

REVEL

Benign

0.12

Sift

Benign

0.66

.;T;T

Sift4G

Benign

0.077

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.20

MVP

0.80

MPC

0.13

ClinPred

0.070

GERP RS

5.1

Varity_R

0.12

gMVP

0.29

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