9-34459053-G-T

Position:

• chr9-34459053-G-T

Variant summary

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

The NM_012144.4(DNAI1):​c.48G>T​(p.Gln16His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAI1 NM_012144.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAI1	NM_012144.4	c.48G>T	p.Gln16His	missense_variant, splice_region_variant	1/20	ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2	c.48G>T	p.Gln16His	missense_variant, splice_region_variant	1/20		NP_001268357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAI1	ENST00000242317.9	c.48G>T	p.Gln16His	missense_variant, splice_region_variant	1/20	1	NM_012144.4	ENSP00000242317.4
DNAI1	ENST00000614641.4	c.48G>T	p.Gln16His	missense_variant, splice_region_variant	1/20	5		ENSP00000480538.1
DNAI1	ENST00000437363.5	c.48G>T	p.Gln16His	missense_variant, splice_region_variant	1/9	5		ENSP00000395396.1
DNAI1	ENST00000470982.5	n.47+1593G>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2022

The c.48G>T variant (also known as p.Q16H), located in coding exon 1 of the DNAI1 gene, results from a G to T substitution at nucleotide position 48. The glutamine at codon 16 is replaced by histidine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	T;T;T
Eigen	Benign	-0.096
Eigen_PC	Benign	0.069
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.34	.;.;N
MutationTaster	Benign	0.78	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	.;N;N
REVEL	Benign	0.11
Sift	Benign	0.044	.;D;T
Sift4G	Benign	0.12	T;D;T
Polyphen		0.0	.;.;B
Vest4		0.20
MutPred		0.14		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.85
MPC		0.10
ClinPred		0.54	D
GERP RS		5.1
Varity_R		0.18
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-34459051;