rs45529837

Variant names:

• chr6-38789839-G-A
• rs45529837
• NM_001206927.2:c.2620G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001206927.2(DNAH8):​c.2620G>A​(p.Val874Met) variant causes a missense change. The variant allele was found at a frequency of 0.0289 in 1,612,376 control chromosomes in the GnomAD database, including 791 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (67 hom., cov: 33)
  • Exomes 𝑓: 0.029 (724 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.58
• Publications: 12 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: ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003100425).
• BP6: Variant 6-38789839-G-A is Benign according to our data. Variant chr6-38789839-G-A is described in ClinVar as Benign. ClinVar VariationId is 414389.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.061 is higher than 0.05.

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.2620G>A	p.Val874Met	missense	Exon 19 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.1969G>A	p.Val657Met	missense	Exon 18 of 92	NP_001362.2	Q96JB1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.2620G>A	p.Val874Met	missense	Exon 19 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.1969G>A	p.Val657Met	missense	Exon 17 of 91	ENSP00000352312.3	Q96JB1-1
	DNAH8	ENST00000449981.6	TSL:5	c.2620G>A	p.Val874Met	missense	Exon 18 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3967 AN: 152154 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.000961

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0516

GnomAD2 exomes AF: 0.0249 AC: 6238 AN: 250822 AF XY: 0.0256

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.0310

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0351

GnomAD4 exome AF: 0.0292 AC: 42676 AN: 1460104 Hom.: 724 Cov.: 30 AF XY: 0.0290 AC XY: 21089 AN XY: 726444

African (AFR) AF: 0.0127 AC: 426 AN: 33448

American (AMR) AF: 0.0308 AC: 1370 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 846 AN: 26114

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39624

South Asian (SAS) AF: 0.0166 AC: 1433 AN: 86090

European-Finnish (FIN) AF: 0.0215 AC: 1149 AN: 53410

Middle Eastern (MID) AF: 0.0664 AC: 383 AN: 5764

European-Non Finnish (NFE) AF: 0.0318 AC: 35298 AN: 1110812

Other (OTH) AF: 0.0293 AC: 1768 AN: 60324

GnomAD4 genome AF: 0.0260 AC: 3958 AN: 152272 Hom.: 67 Cov.: 33 AF XY: 0.0259 AC XY: 1926 AN XY: 74458

African (AFR) AF: 0.0142 AC: 591 AN: 41568

American (AMR) AF: 0.0436 AC: 667 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3468

East Asian (EAS) AF: 0.000963 AC: 5 AN: 5192

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4816

European-Finnish (FIN) AF: 0.0219 AC: 232 AN: 10604

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0307 AC: 2087 AN: 68012

Other (OTH) AF: 0.0510 AC: 108 AN: 2116

Alfa AF: 0.0294 Hom.: 216

Bravo AF: 0.0284

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.0343 AC: 295

ExAC AF: 0.0250 AC: 3034

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0327

EpiControl AF: 0.0362

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.085
Sift	Benign	0.19	T
Polyphen		0.12	B
Vest4		0.23
MPC		0.47
ClinPred		0.011	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.26
Mutation Taster		=97/3	polymorphism (auto)

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: rs45529837; hg19: chr6-38757615;