rs200411544

Positions:

• chr9-34483484-AG-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_012144.4(DNAI1):​c.81+5delG variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00113 in 1,612,148 control chromosomes in the GnomAD database, including 34 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (26 hom.)
• Consequence: DNAI1 NM_012144.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.78

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 9-34483484-AG-A is Benign according to our data. Variant chr9-34483484-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95492.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0019 (289/152340) while in subpopulation AMR AF= 0.0161 (246/15296). AF 95% confidence interval is 0.0144. There are 8 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI1	NM_012144.4	c.81+5delG		splice_region_variant, intron_variant		ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2	c.81+5delG		splice_region_variant, intron_variant			NP_001268357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI1	ENST00000242317.9	c.81+5delG		splice_region_variant, intron_variant		1	NM_012144.4	ENSP00000242317.4
DNAI1	ENST00000614641.4	c.81+5delG		splice_region_variant, intron_variant		5		ENSP00000480538.1
DNAI1	ENST00000437363.5	c.49-1657delG		intron_variant		5		ENSP00000395396.1
DNAI1	ENST00000470982.5	n.80+5delG		splice_region_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152222 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00431 AC: 1077 AN: 249806 Hom.: 24 AF XY: 0.00313 AC XY: 423 AN XY: 135142

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.0296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00104 AC: 1525 AN: 1459808 Hom.: 26 Cov.: 30 AF XY: 0.000877 AC XY: 637 AN XY: 726286

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.0274

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00514

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152340 Hom.: 8 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74510

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.00328

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 03, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2013	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 10, 2018

The c.81+5delG variant in DNAI1 is classified as benign because it has been iden tified in 3% (1022/34400) of Latino chromosomes, including 23 homozygotes, by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP r s200411544). This deletion occurs within the splice site consensus sequence and is predicted to impact splicing by computational prediction tools. ACMG/AMP Crit eria applied: BA1; PP3. -

DNAI1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Kartagener syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200411544; hg19: chr9-34483482;