9-34459027-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012144.4(DNAI1):c.22G>T(p.Ala8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0616 in 1,613,884 control chromosomes in the GnomAD database, including 3,592 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. A8P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.050 (271 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3321 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.40

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016712248).
• BP6: Variant 9-34459027-G-T is Benign according to our data. Variant chr9-34459027-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 178761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34459027-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4	c.22G>T	p.Ala8Ser	missense_variant	1/20	ENST00000242317.9
DNAI1	NM_001281428.2	c.22G>T	p.Ala8Ser	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9	c.22G>T	p.Ala8Ser	missense_variant	1/20	1	NM_012144.4
DNAI1	ENST00000614641.4	c.22G>T	p.Ala8Ser	missense_variant	1/20	5		P1
DNAI1	ENST00000437363.5	c.22G>T	p.Ala8Ser	missense_variant	1/9	5
DNAI1	ENST00000470982.5	n.47+1567G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0496 AC: 7547 AN: 152090 Hom.: 271 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0460

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.00789

Gnomad SAS AF: 0.0448

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0550 AC: 13820 AN: 251398 Hom.: 471 AF XY: 0.0558 AC XY: 7584 AN XY: 135880

Gnomad AFR exome AF: 0.0124

Gnomad AMR exome AF: 0.0439

Gnomad ASJ exome AF: 0.0416

Gnomad EAS exome AF: 0.00674

Gnomad SAS exome AF: 0.0520

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.0625

Gnomad OTH exome AF: 0.0611

GnomAD4 exome AF: 0.0629 AC: 91923 AN: 1461676 Hom.: 3321 Cov.: 31 AF XY: 0.0627 AC XY: 45619 AN XY: 727142

Gnomad4 AFR exome AF: 0.00995

Gnomad4 AMR exome AF: 0.0443

Gnomad4 ASJ exome AF: 0.0419

Gnomad4 EAS exome AF: 0.00491

Gnomad4 SAS exome AF: 0.0532

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.0667

Gnomad4 OTH exome AF: 0.0565

GnomAD4 genome AF: 0.0496 AC: 7546 AN: 152208 Hom.: 271 Cov.: 32 AF XY: 0.0505 AC XY: 3758 AN XY: 74404

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.0461

Gnomad4 ASJ AF: 0.0473

Gnomad4 EAS AF: 0.00772

Gnomad4 SAS AF: 0.0448

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.0650

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0512 Hom.: 199

Bravo AF: 0.0413

TwinsUK AF: 0.0693 AC: 257

ALSPAC AF: 0.0701 AC: 270

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.0630 AC: 542

ExAC AF: 0.0540 AC: 6553

Asia WGS AF: 0.0220 AC: 78 AN: 3478

EpiCase AF: 0.0614

EpiControl AF: 0.0563

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2014	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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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	Ala8Ser in exon 1 of DNAI1: This variant is not expected to have clinical signif icance because it has been identified in 6.3% (542/8600) of European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs11547035). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.7
Dann	Benign	0.79
DEOGEN2	Benign	0.0076	T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.32	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.70	T;T;T
Polyphen		0.0020	.;.;B
Vest4		0.080
MPC		0.10
ClinPred		0.012	T
GERP RS		2.6
Varity_R		0.043
gMVP		0.093

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

Other links and lift over

dbSNP: rs11547035; hg19: chr9-34459025;