rs146501326

chr9-34459045-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_012144.4(DNAI1):c.40C>T(p.His14Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000954 in 1,614,046 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (2 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.90

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017238647).
• BP6: Variant 9-34459045-C-T is Benign according to our data. Variant chr9-34459045-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 580210.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4	c.40C>T	p.His14Tyr	missense_variant	1/20	ENST00000242317.9
DNAI1	NM_001281428.2	c.40C>T	p.His14Tyr	missense_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9	c.40C>T	p.His14Tyr	missense_variant	1/20	1	NM_012144.4
DNAI1	ENST00000614641.4	c.40C>T	p.His14Tyr	missense_variant	1/20	5		P1
DNAI1	ENST00000437363.5	c.40C>T	p.His14Tyr	missense_variant	1/9	5
DNAI1	ENST00000470982.5	n.47+1585C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251374 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135870

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461838 Hom.: 2 Cov.: 30 AF XY: 0.0000481 AC XY: 35 AN XY: 727220

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74362

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000631

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 22, 2018	The p.H14Y variant (also known as c.40C>T), located in coding exon 1 of the DNAI1 gene, results from a C to T substitution at nucleotide position 40. The histidine at codon 14 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is poorly 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 alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Benign	0.79
DEOGEN2	Benign	0.010	T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.36	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.83	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.077	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.20
MVP		0.80
MPC		0.13
ClinPred		0.070	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.29

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: rs146501326; hg19: chr9-34459043;