rs3744581

Variant names:

• chr17-11747740-A-G
• rs3744581
• NM_001372.4:c.6584A>G

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.6584A>G​(p.Asn2195Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,613,082 control chromosomes in the GnomAD database, including 39,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3390 hom., cov: 31)
  • Exomes 𝑓: 0.22 (36387 hom.)
• Consequence: DNAH9 NM_001372.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.48
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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=0.0018789768).
• BP6: Variant 17-11747740-A-G is Benign according to our data. Variant chr17-11747740-A-G is described in ClinVar as Benign. ClinVar VariationId is 402778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH9	NM_001372.4	MANE Select	c.6584A>G	p.Asn2195Ser	missense	Exon 32 of 69	NP_001363.2	Q9NYC9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH9	ENST00000262442.9	TSL:1 MANE Select	c.6584A>G	p.Asn2195Ser	missense	Exon 32 of 69	ENSP00000262442.3	Q9NYC9-1
	DNAH9	ENST00000454412.6	TSL:5	c.6584A>G	p.Asn2195Ser	missense	Exon 32 of 68	ENSP00000414874.2	E7EP17

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31333 AN: 152014 Hom.: 3383 Cov.: 31

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.224

GnomAD2 exomes AF: 0.221 AC: 55459 AN: 250952 AF XY: 0.222

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.366

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.220 AC: 321009 AN: 1460950 Hom.: 36387 Cov.: 34 AF XY: 0.219 AC XY: 159378 AN XY: 726786

African (AFR) AF: 0.160 AC: 5341 AN: 33466

American (AMR) AF: 0.203 AC: 9079 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6107 AN: 26124

East Asian (EAS) AF: 0.375 AC: 14880 AN: 39690

South Asian (SAS) AF: 0.187 AC: 16140 AN: 86218

European-Finnish (FIN) AF: 0.170 AC: 9051 AN: 53372

Middle Eastern (MID) AF: 0.251 AC: 1440 AN: 5738

European-Non Finnish (NFE) AF: 0.221 AC: 245919 AN: 1111272

Other (OTH) AF: 0.216 AC: 13052 AN: 60368

GnomAD4 genome AF: 0.206 AC: 31354 AN: 152132 Hom.: 3390 Cov.: 31 AF XY: 0.203 AC XY: 15131 AN XY: 74370

African (AFR) AF: 0.160 AC: 6628 AN: 41538

American (AMR) AF: 0.232 AC: 3542 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 790 AN: 3468

East Asian (EAS) AF: 0.351 AC: 1811 AN: 5154

South Asian (SAS) AF: 0.189 AC: 908 AN: 4810

European-Finnish (FIN) AF: 0.159 AC: 1687 AN: 10590

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15294 AN: 67988

Other (OTH) AF: 0.222 AC: 467 AN: 2108

Alfa AF: 0.228 Hom.: 18254

Bravo AF: 0.211

TwinsUK AF: 0.230 AC: 854

ALSPAC AF: 0.215 AC: 827

ESP6500AA AF: 0.162 AC: 712

ESP6500EA AF: 0.244 AC: 2099

ExAC AF: 0.222 AC: 26902

Asia WGS AF: 0.261 AC: 909 AN: 3478

EpiCase AF: 0.240

EpiControl AF: 0.241

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Ciliary dyskinesia, primary, 40 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.3	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.5
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.61
Sift	Benign	0.036	D
Polyphen		0.87	P
Vest4		0.17
MPC		0.20
ClinPred		0.070	T
GERP RS		3.3
Varity_R		0.24
gMVP		0.20
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3744581; hg19: chr17-11651057; COSMIC: COSV52349954;