rs11999454

chr9-34512395-T-G

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.1460T>G(p.Val487Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0127 in 1,614,028 control chromosomes in the GnomAD database, including 846 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (139 hom., cov: 32)
  • Exomes 𝑓: 0.011 (707 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.84

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=0.001478523).
• BP6: Variant 9-34512395-T-G is Benign according to our data. Variant chr9-34512395-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 163165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34512395-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4	c.1460T>G	p.Val487Gly	missense_variant	15/20	ENST00000242317.9
DNAI1	NM_001281428.2	c.1472T>G	p.Val491Gly	missense_variant	15/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9	c.1460T>G	p.Val487Gly	missense_variant	15/20	1	NM_012144.4
DNAI1	ENST00000614641.4	c.1472T>G	p.Val491Gly	missense_variant	15/20	5		P1
DNAI1	ENST00000470169.5	c.398T>G	p.Val133Gly	missense_variant, NMD_transcript_variant	3/6	5

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4294 AN: 152036 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0463

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0344 AC: 8656 AN: 251300 Hom.: 456 AF XY: 0.0290 AC XY: 3935 AN XY: 135830

Gnomad AFR exome AF: 0.0644

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.131

Gnomad SAS exome AF: 0.0248

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0110 AC: 16142 AN: 1461874 Hom.: 707 Cov.: 33 AF XY: 0.0107 AC XY: 7789 AN XY: 727234

Gnomad4 AFR exome AF: 0.0650

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.0234

Gnomad4 FIN exome AF: 0.0121

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0283 AC: 4310 AN: 152154 Hom.: 139 Cov.: 32 AF XY: 0.0290 AC XY: 2158 AN XY: 74384

Gnomad4 AFR AF: 0.0610

Gnomad4 AMR AF: 0.0464

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.0270

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.00159

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0121 Hom.: 123

Bravo AF: 0.0363

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0611 AC: 269

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0328 AC: 3978

Asia WGS AF: 0.0770 AC: 265 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 12, 2015	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	Invitae	Feb 01, 2024	- -

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	Val487Gly in exon 15 of DNAI1: This variant is not expected to have clinical sig nificance because it has been identified in 6.1% (269/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs11999454). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Kartagener syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Counsyl

Mar 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	13
Dann	Benign	0.87
DEOGEN2	Benign	0.0033	T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.023
MPC		0.15
ClinPred		0.00073	T
GERP RS		3.5
Varity_R		0.042
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs11999454; hg19: chr9-34512393; COSMIC: COSV54279474; COSMIC: COSV54279474;