rs17612861

Variant names:

• chr17-11932014-G-A
• rs17612861
• NM_001372.4:c.12106G>A

Variant summary

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

The NM_001372.4(DNAH9):​c.12106G>A​(p.Asp4036Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.304 in 1,613,426 control chromosomes in the GnomAD database, including 77,786 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5493 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72293 hom.)
• Consequence: DNAH9 NM_001372.4 missense, splice_region
• Scores: Splicing: ADA: 0.2767
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.79
• Publications: 26 publications found

Genes affected

DNAH9 (HGNC:2953): (dynein axonemal heavy chain 9) This gene encodes the heavy chain subunit of axonemal dynein, a large multi-subunit molecular motor. Axonemal dynein attaches to microtubules and hydrolyzes ATP to mediate the movement of cilia and flagella. The gene expresses at least two transcript variants; additional variants have been described, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

DNAH9 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 40

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• situs inversus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• schizophrenia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017387867).
• BP6: Variant 17-11932014-G-A is Benign according to our data. Variant chr17-11932014-G-A is described in ClinVar as Benign. ClinVar VariationId is 402787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH9	NM_001372.4	MANE Select	c.12106G>A	p.Asp4036Asn	missense splice_region	Exon 64 of 69	NP_001363.2
	DNAH9	NM_004662.2		c.1042G>A	p.Asp348Asn	missense splice_region	Exon 10 of 15	NP_004653.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH9	ENST00000262442.9	TSL:1 MANE Select	c.12106G>A	p.Asp4036Asn	missense splice_region	Exon 64 of 69	ENSP00000262442.3
	DNAH9	ENST00000608377.5	TSL:1	c.1042G>A	p.Asp348Asn	missense splice_region	Exon 10 of 15	ENSP00000476951.1
	DNAH9	ENST00000396001.6	TSL:1	n.1569G>A		splice_region non_coding_transcript_exon	Exon 10 of 15

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37511 AN: 151926 Hom.: 5493 Cov.: 32

Gnomad AFR AF: 0.0762

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.331

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.286

GnomAD2 exomes AF: 0.284 AC: 71286 AN: 251116 AF XY: 0.293

Gnomad AFR exome AF: 0.0713

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.361

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.332

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.309 AC: 452194 AN: 1461382 Hom.: 72293 Cov.: 37 AF XY: 0.312 AC XY: 226785 AN XY: 726968

African (AFR) AF: 0.0628 AC: 2103 AN: 33476

American (AMR) AF: 0.208 AC: 9319 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 9281 AN: 26122

East Asian (EAS) AF: 0.165 AC: 6548 AN: 39688

South Asian (SAS) AF: 0.313 AC: 26964 AN: 86236

European-Finnish (FIN) AF: 0.319 AC: 17035 AN: 53410

Middle Eastern (MID) AF: 0.341 AC: 1962 AN: 5748

European-Non Finnish (NFE) AF: 0.325 AC: 360817 AN: 1111624

Other (OTH) AF: 0.301 AC: 18165 AN: 60370

GnomAD4 genome AF: 0.247 AC: 37503 AN: 152044 Hom.: 5493 Cov.: 32 AF XY: 0.247 AC XY: 18366 AN XY: 74308

African (AFR) AF: 0.0761 AC: 3156 AN: 41498

American (AMR) AF: 0.250 AC: 3819 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1218 AN: 3472

East Asian (EAS) AF: 0.194 AC: 1000 AN: 5164

South Asian (SAS) AF: 0.317 AC: 1519 AN: 4792

European-Finnish (FIN) AF: 0.318 AC: 3362 AN: 10560

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.331 AC: 22506 AN: 67968

Other (OTH) AF: 0.282 AC: 596 AN: 2110

Alfa AF: 0.301 Hom.: 21259

Bravo AF: 0.230

TwinsUK AF: 0.316 AC: 1172

ALSPAC AF: 0.326 AC: 1257

ESP6500AA AF: 0.0840 AC: 370

ESP6500EA AF: 0.334 AC: 2876

ExAC AF: 0.286 AC: 34759

Asia WGS AF: 0.220 AC: 762 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Uncertain	25
DANN	Benign	0.29
DEOGEN2	Benign	0.062	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.13
Sift	Benign	0.088	T
Sift4G	Benign	0.12	T
Polyphen		0.19	B
Vest4		0.26
MPC		0.13
ClinPred		0.041	T
GERP RS		3.8
Varity_R		0.37
gMVP		0.28
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.28
dbscSNV1_RF	Benign	0.49
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: rs17612861; hg19: chr17-11835331; COSMIC: COSV52341645;