chr17-11598540-C-A

Variant names:

• chr17-11598540-C-A
• rs377715895
• NM_001372.4:c.42C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001372.4(DNAH9):​c.42C>A​(p.Asn14Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000796 in 1,255,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: DNAH9 NM_001372.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.735
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053346187).

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.42C>A	p.Asn14Lys	missense	Exon 1 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.42C>A	p.Asn14Lys	missense	Exon 1 of 69	ENSP00000262442.3	Q9NYC9-1
	DNAH9	ENST00000579406.1	TSL:1	n.69C>A		non_coding_transcript_exon	Exon 1 of 8
	DNAH9	ENST00000454412.6	TSL:5	c.42C>A	p.Asn14Lys	missense	Exon 1 of 68	ENSP00000414874.2	E7EP17

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.96e-7 AC: 1 AN: 1255522 Hom.: 0 Cov.: 33 AF XY: 0.00000163 AC XY: 1 AN XY: 613442

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25026

American (AMR) AF: 0.0000623 AC: 1 AN: 16040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19250

East Asian (EAS) AF: 0.00 AC: 0 AN: 28050

South Asian (SAS) AF: 0.00 AC: 0 AN: 60558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1020620

Other (OTH) AF: 0.00 AC: 0 AN: 51760

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.52
DANN	Benign	0.57
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N
PhyloP100		-0.73
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.016
Sift	Benign	0.79	T
Sift4G	Uncertain	0.036	D
Polyphen		0.0	B
Vest4		0.10
MutPred		0.28		Gain of ubiquitination at N14 (P = 0.0029)
MVP		0.13
MPC		0.11
ClinPred		0.036	T
GERP RS		-0.63
PromoterAI		0.075	Neutral
Varity_R		0.032
gMVP		0.27
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs377715895; hg19: chr17-11501857;