rs138460682

Positions:

• chr9-34520701-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012144.4(DNAI1):​c.2045T>C​(p.Ile682Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000554 in 1,551,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.18

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15934876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI1	NM_012144.4	c.2045T>C	p.Ile682Thr	missense_variant	20/20	ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2	c.2057T>C	p.Ile686Thr	missense_variant	20/20		NP_001268357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI1	ENST00000242317.9	c.2045T>C	p.Ile682Thr	missense_variant	20/20	1	NM_012144.4	ENSP00000242317.4
DNAI1	ENST00000614641.4	c.2057T>C	p.Ile686Thr	missense_variant	20/20	5		ENSP00000480538.1
DNAI1	ENST00000442556.1	c.371T>C	p.Ile124Thr	missense_variant	4/4	5		ENSP00000408129.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 18 AN: 156096 Hom.: 0 AF XY: 0.0000973 AC XY: 8 AN XY: 82182

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000219

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000457 AC: 64 AN: 1399436 Hom.: 0 Cov.: 31 AF XY: 0.0000507 AC XY: 35 AN XY: 690238

Gnomad4 AFR exome AF: 0.000222

Gnomad4 AMR exome AF: 0.000308

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.000215

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.0000232

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74406

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.000130 AC: 1

ExAC AF: 0.0000516 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 22, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 682 of the DNAI1 protein (p.Ile682Thr). This variant is present in population databases (rs138460682, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 454834). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 07, 2015	The p.I682T variant (also known as c.2045T>C), located in coding exon 20 of the DNAI1 gene, results from a T to C substitution at nucleotide position 2045. The isoleucine at codon 682 is replaced by threonine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs138460682. Based on data from the 1000 Genomes Project, the C allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.94% (1/106) African-American SW alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 0.02% (2/11692) total alleles studied, having been observed in 0.02% (1/4016) African American alleles and 0.01% (1/7676) European American alleles. This amino acid position is well 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 variant remains unclear. -

DNAI1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 14, 2023

The DNAI1 c.2045T>C variant is predicted to result in the amino acid substitution p.Ile682Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.035% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-34520699-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	T;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	.;N
REVEL	Uncertain	0.39
Sift	Benign	0.087	.;T
Sift4G	Benign	0.15	T;T
Polyphen		0.90	.;P
Vest4		0.39
MVP		0.91
MPC		0.19
ClinPred		0.11	T
GERP RS		5.5
Varity_R		0.13
gMVP		0.43

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

Other links and lift over

dbSNP: rs138460682; hg19: chr9-34520699;