chr9-34458826-G-A

Position:

• chr9-34458826-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_012144.4(DNAI1):​c.-180G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000614 in 671,388 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: DNAI1 NM_012144.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00194 (295/152348) while in subpopulation AFR AF= 0.00661 (275/41592). AF 95% confidence interval is 0.00597. There are 1 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI1	NM_012144.4	c.-180G>A		5_prime_UTR_variant	1/20	ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2	c.-180G>A		5_prime_UTR_variant	1/20		NP_001268357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI1	ENST00000242317	c.-180G>A		5_prime_UTR_variant	1/20	1	NM_012144.4	ENSP00000242317.4
DNAI1	ENST00000614641	c.-180G>A		5_prime_UTR_variant	1/20	5		ENSP00000480538.1
DNAI1	ENST00000470982.5	n.47+1366G>A		intron_variant		5
DNAI1	ENST00000437363.5	c.-180G>A		upstream_gene_variant		5		ENSP00000395396.1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 295 AN: 152230 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00663

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.000225 AC: 117 AN: 519040 Hom.: 0 Cov.: 5 AF XY: 0.000195 AC XY: 54 AN XY: 277124

Gnomad4 AFR exome AF: 0.00590

Gnomad4 AMR exome AF: 0.000349

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000523

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000559

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152348 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74514

Gnomad4 AFR AF: 0.00661

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.00201

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kartagener syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.95

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs180838420; hg19: chr9-34458824;