rs1060503514

Variant names:

• chr9-34489427-T-A
• rs1060503514
• NM_012144.4:c.366T>A

Your query was ambiguous. Multiple possible variants found:

• chr9-34489427-T-A
• chr9-34489427-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012144.4(DNAI1):​c.366T>A​(p.His122Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H122H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.358
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085125655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI1	NM_012144.4	c.366T>A	p.His122Gln	missense_variant	Exon 5 of 20	ENST00000242317.9	NP_036276.1
DNAI1	NM_001281428.2	c.366T>A	p.His122Gln	missense_variant	Exon 5 of 20		NP_001268357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAI1	ENST00000242317.9	c.366T>A	p.His122Gln	missense_variant	Exon 5 of 20	1	NM_012144.4	ENSP00000242317.4
DNAI1	ENST00000614641.4	c.366T>A	p.His122Gln	missense_variant	Exon 5 of 20	5		ENSP00000480538.1
DNAI1	ENST00000437363.5	c.333T>A	p.His111Gln	missense_variant	Exon 4 of 9	5		ENSP00000395396.1
DNAI1	ENST00000488369.1	n.482T>A		non_coding_transcript_exon_variant	Exon 5 of 9	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

May 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 411840). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 122 of the DNAI1 protein (p.His122Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Benign	0.0029	T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.085	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;.;L
PhyloP100		0.36
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.37	.;N;N
REVEL	Benign	0.052
Sift	Benign	0.64	.;T;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.36
MutPred		0.30		Loss of helix (P = 0.0138);.;Loss of helix (P = 0.0138);
MVP		0.47
MPC		0.11
ClinPred		0.063	T
GERP RS		-0.52
Varity_R		0.048
gMVP		0.20
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1060503514; hg19: chr9-34489425;