9-34500823-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_012144.4(DNAI1):c.1003G>T(p.Val335Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V335I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.61

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 9-34500823-G-T is Pathogenic according to our data. Variant chr9-34500823-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525451.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAI1	NM_012144.4	c.1003G>T	p.Val335Phe	missense_variant	11/20	ENST00000242317.9
DNAI1	NM_001281428.2	c.1015G>T	p.Val339Phe	missense_variant	11/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAI1	ENST00000242317.9	c.1003G>T	p.Val335Phe	missense_variant	11/20	1	NM_012144.4
DNAI1	ENST00000614641.4	c.1015G>T	p.Val339Phe	missense_variant	11/20	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251262 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461678 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727160

Gnomad4 AFR exome AF: 0.0000299

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

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kartagener syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Jul 19, 2018

- -

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2021

This sequence change replaces valine with phenylalanine at codon 335 of the DNAI1 protein (p.Val335Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs11793196, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of DNAI1-related conditions (PMID: 30868567). 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: "Possibly Damaging"; 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.65	D
MutationTaster	Benign	0.0000023	P
PrimateAI	Benign	0.48	T
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.99	.;D
Vest4		0.91
MutPred		0.39		.;Gain of MoRF binding (P = 0.1396);
MVP		0.93
MPC		0.43
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.79
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11793196; hg19: chr9-34500821;