rs3818577

Variant names:

• chr9-34489439-A-G
• rs3818577
• NM_012144.4:c.378A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012144.4(DNAI1):​c.378A>G​(p.Glu126Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,613,670 control chromosomes in the GnomAD database, including 758 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (97 hom., cov: 32)
  • Exomes 𝑓: 0.010 (661 hom.)
• Consequence: DNAI1 NM_012144.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.142
• Publications: 7 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), PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-34489439-A-G is Benign according to our data. Variant chr9-34489439-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.142 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

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.378A>G	p.Glu126Glu	synonymous	Exon 5 of 20	NP_036276.1	A0A140VJI0
	DNAI1	NM_001281428.2		c.378A>G	p.Glu126Glu	synonymous	Exon 5 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.378A>G	p.Glu126Glu	synonymous	Exon 5 of 20	ENSP00000242317.4	Q9UI46-1
	DNAI1	ENST00000878474.1		c.471A>G	p.Glu157Glu	synonymous	Exon 6 of 21	ENSP00000548533.1
	DNAI1	ENST00000614641.4	TSL:5	c.378A>G	p.Glu126Glu	synonymous	Exon 5 of 20	ENSP00000480538.1	A0A087WWV9

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3334 AN: 152150 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0433

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0325 AC: 8179 AN: 251476 AF XY: 0.0274

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0102 AC: 14895 AN: 1461402 Hom.: 661 Cov.: 31 AF XY: 0.00992 AC XY: 7215 AN XY: 726996

African (AFR) AF: 0.0406 AC: 1360 AN: 33458

American (AMR) AF: 0.101 AC: 4498 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26130

East Asian (EAS) AF: 0.113 AC: 4483 AN: 39682

South Asian (SAS) AF: 0.0236 AC: 2031 AN: 86232

European-Finnish (FIN) AF: 0.0121 AC: 647 AN: 53390

Middle Eastern (MID) AF: 0.0105 AC: 58 AN: 5532

European-Non Finnish (NFE) AF: 0.000836 AC: 930 AN: 1111908

Other (OTH) AF: 0.0147 AC: 885 AN: 60350

GnomAD4 genome AF: 0.0220 AC: 3355 AN: 152268 Hom.: 97 Cov.: 32 AF XY: 0.0230 AC XY: 1715 AN XY: 74470

African (AFR) AF: 0.0401 AC: 1667 AN: 41538

American (AMR) AF: 0.0433 AC: 663 AN: 15300

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

East Asian (EAS) AF: 0.120 AC: 623 AN: 5178

South Asian (SAS) AF: 0.0265 AC: 128 AN: 4832

European-Finnish (FIN) AF: 0.0124 AC: 132 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68018

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.0115 Hom.: 98

Bravo AF: 0.0285

Asia WGS AF: 0.0760 AC: 262 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Primary ciliary dyskinesia (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Kartagener syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.29
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3818577; hg19: chr9-34489437; COSMIC: COSV54278820; COSMIC: COSV54278820;