rs11793196

chr9-34500823-G-Achr9-34500823-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_012144.4(DNAI1):c.1003G>A(p.Val335Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,613,248 control chromosomes in the GnomAD database, including 20,995 homozygotes. In-silico tool predicts 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. V335F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.20 (3449 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17546 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.61

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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-34500823-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525451.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015288591).
• BP6: Variant 9-34500823-G-A is Benign according to our data. Variant chr9-34500823-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34500823-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4	c.1003G>A	p.Val335Ile	missense_variant	11/20	ENST00000242317.9
DNAI1	NM_001281428.2	c.1015G>A	p.Val339Ile	missense_variant	11/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9	c.1003G>A	p.Val335Ile	missense_variant	11/20	1	NM_012144.4
DNAI1	ENST00000614641.4	c.1015G>A	p.Val339Ile	missense_variant	11/20	5		P1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29683 AN: 152068 Hom.: 3445 Cov.: 32

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.153 AC: 38388 AN: 251262 Hom.: 3459 AF XY: 0.149 AC XY: 20211 AN XY: 135800

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.157

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.00886

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.149 AC: 218086 AN: 1461062 Hom.: 17546 Cov.: 32 AF XY: 0.149 AC XY: 108235 AN XY: 726868

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.0129

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.154

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.157

GnomAD4 genome AF: 0.195 AC: 29714 AN: 152186 Hom.: 3449 Cov.: 32 AF XY: 0.192 AC XY: 14274 AN XY: 74414

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.144

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.186

Alfa AF: 0.149 Hom.: 4802

Bravo AF: 0.202

TwinsUK AF: 0.144 AC: 535

ALSPAC AF: 0.153 AC: 591

ESP6500AA AF: 0.322 AC: 1420

ESP6500EA AF: 0.152 AC: 1308

ExAC AF: 0.156 AC: 18945

Asia WGS AF: 0.108 AC: 375 AN: 3478

EpiCase AF: 0.148

EpiControl AF: 0.149

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

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 11, 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:3

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	Val335Ile in exon 11 of DNAI1: This variant is not expected to have clinical sig nificance because it has been identified in 32.2% (1420/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs11793196). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Kartagener syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.074	T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.000089	P
PrimateAI	Benign	0.38	T
Sift4G	Uncertain	0.036	D;D
Polyphen		0.19	.;B
Vest4		0.17
MPC		0.10
ClinPred		0.052	T
GERP RS		5.0
Varity_R		0.083
gMVP		0.53

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: rs11793196; hg19: chr9-34500821;