9-34493232-G-T

Variant names:

• chr9-34493232-G-T
• rs999905460
• NM_012144.4:c.720G>T

Variant summary

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

The NM_012144.4(DNAI1):​c.720G>T​(p.Lys240Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.397
• 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: ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012144.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI1	NM_012144.4	MANE Select	c.720G>T	p.Lys240Asn	missense	Exon 9 of 20	NP_036276.1	A0A140VJI0
	DNAI1	NM_001281428.2		c.732G>T	p.Lys244Asn	missense	Exon 9 of 20	NP_001268357.1	A0A087WWV9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAI1	ENST00000242317.9	TSL:1 MANE Select	c.720G>T	p.Lys240Asn	missense	Exon 9 of 20	ENSP00000242317.4	Q9UI46-1
	DNAI1	ENST00000878474.1		c.813G>T	p.Lys271Asn	missense	Exon 10 of 21	ENSP00000548533.1
	DNAI1	ENST00000614641.4	TSL:5	c.732G>T	p.Lys244Asn	missense	Exon 9 of 20	ENSP00000480538.1	A0A087WWV9

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74356

African (AFR) AF: 0.000121 AC: 5 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.050
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.40
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.057	T
Polyphen		0.98	D
Vest4		0.36
MutPred		0.35		Loss of ubiquitination at K240 (P = 0.0092)
MVP		0.87
MPC		0.17
ClinPred		0.89	D
GERP RS		-0.41
Varity_R		0.17
gMVP		0.53
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -38

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

Other links and lift over

dbSNP: rs999905460; hg19: chr9-34493230;