rs1554130647

Variant names:

• chr6-38898324-A-G
• rs1554130647
• NM_001206927.2:c.9007A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001206927.2(DNAH8):​c.9007A>G​(p.Arg3003Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33
• Publications: 0 publications found

Genes affected

DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]

DNAH8 Gene-Disease associations (from GenCC):

• spermatogenic failure 46

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• spermatogenic failure 5

  Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
• primary ciliary dyskinesia

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206927.2. 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
	DNAH8	NM_001206927.2	MANE Select	c.9007A>G	p.Arg3003Gly	missense	Exon 61 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.8356A>G	p.Arg2786Gly	missense	Exon 60 of 92	NP_001362.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.9007A>G	p.Arg3003Gly	missense	Exon 61 of 93	ENSP00000333363.7
	DNAH8	ENST00000359357.7	TSL:2	c.8356A>G	p.Arg2786Gly	missense	Exon 59 of 91	ENSP00000352312.3
	DNAH8	ENST00000449981.6	TSL:5	c.9007A>G	p.Arg3003Gly	missense	Exon 60 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1437980 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 714438

African (AFR) AF: 0.0000314 AC: 1 AN: 31876

American (AMR) AF: 0.00 AC: 0 AN: 39422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25718

East Asian (EAS) AF: 0.00 AC: 0 AN: 38298

South Asian (SAS) AF: 0.00 AC: 0 AN: 79660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1104570

Other (OTH) AF: 0.00 AC: 0 AN: 59558

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.51		Loss of loop (P = 0.0804)
MVP		0.69
MPC		0.64
ClinPred		1.0	D
GERP RS		0.27
Varity_R		0.81
gMVP		0.61
Mutation Taster		=62/38	polymorphism

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: rs1554130647; hg19: chr6-38866100;