chr9-34512395-T-G

Variant names:

• chr9-34512395-T-G
• rs11999454
• NM_012144.4:c.1460T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012144.4(DNAI1):​c.1460T>G​(p.Val487Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0127 in 1,614,028 control chromosomes in the GnomAD database, including 846 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (139 hom., cov: 32)
  • Exomes 𝑓: 0.011 (707 hom.)
• Consequence: DNAI1 NM_012144.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.84
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001478523).
• BP6: Variant 9-34512395-T-G is Benign according to our data. Variant chr9-34512395-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.113 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.1460T>G	p.Val487Gly	missense	Exon 15 of 20	NP_036276.1	A0A140VJI0
	DNAI1	NM_001281428.2		c.1472T>G	p.Val491Gly	missense	Exon 15 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.1460T>G	p.Val487Gly	missense	Exon 15 of 20	ENSP00000242317.4	Q9UI46-1
	DNAI1	ENST00000878474.1		c.1553T>G	p.Val518Gly	missense	Exon 16 of 21	ENSP00000548533.1
	DNAI1	ENST00000614641.4	TSL:5	c.1472T>G	p.Val491Gly	missense	Exon 15 of 20	ENSP00000480538.1	A0A087WWV9

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4294 AN: 152036 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0463

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.0274

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0344 AC: 8656 AN: 251300 AF XY: 0.0290

Gnomad AFR exome AF: 0.0644

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.0137

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0110 AC: 16142 AN: 1461874 Hom.: 707 Cov.: 33 AF XY: 0.0107 AC XY: 7789 AN XY: 727234

African (AFR) AF: 0.0650 AC: 2175 AN: 33480

American (AMR) AF: 0.102 AC: 4552 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00191 AC: 50 AN: 26136

East Asian (EAS) AF: 0.113 AC: 4489 AN: 39696

South Asian (SAS) AF: 0.0234 AC: 2014 AN: 86252

European-Finnish (FIN) AF: 0.0121 AC: 649 AN: 53420

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5768

European-Non Finnish (NFE) AF: 0.00105 AC: 1163 AN: 1112008

Other (OTH) AF: 0.0163 AC: 987 AN: 60396

GnomAD4 genome AF: 0.0283 AC: 4310 AN: 152154 Hom.: 139 Cov.: 32 AF XY: 0.0290 AC XY: 2158 AN XY: 74384

African (AFR) AF: 0.0610 AC: 2532 AN: 41514

American (AMR) AF: 0.0464 AC: 710 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.121 AC: 625 AN: 5174

South Asian (SAS) AF: 0.0270 AC: 130 AN: 4822

European-Finnish (FIN) AF: 0.0125 AC: 132 AN: 10582

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 67974

Other (OTH) AF: 0.0260 AC: 55 AN: 2112

Alfa AF: 0.0140 Hom.: 172

Bravo AF: 0.0363

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0611 AC: 269

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0328 AC: 3978

Asia WGS AF: 0.0770 AC: 265 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00231

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.7	N
PhyloP100		3.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	4.3	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.15
ClinPred		0.00073	T
GERP RS		3.5
Varity_R		0.042
gMVP		0.29
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs11999454; hg19: chr9-34512393; COSMIC: COSV54279474; COSMIC: COSV54279474;