9-34517288-C-T

Variant summary

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

The NM_012144.4(DNAI1):c.1822C>T(p.His608Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H608N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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]

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	UniProt
DNAI1	NM_012144.4	c.1822C>T	p.His608Tyr	missense_variant	19/20	ENST00000242317.9
DNAI1	NM_001281428.2	c.1834C>T	p.His612Tyr	missense_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9	c.1822C>T	p.His608Tyr	missense_variant	19/20	1	NM_012144.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461452 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726988

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Invitae

May 11, 2022

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 608 of the DNAI1 protein (p.His608Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.093	T;D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.063	T;T
Polyphen		0.27	.;B
Vest4		0.60
MutPred		0.44		.;Loss of ubiquitination at K606 (P = 0.0982);
MVP		0.87
MPC		0.16
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.35
gMVP		0.63

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: rs148762102; hg19: chr9-34517286;