rs6935293

Variant names:

• chr6-38737167-A-G
• rs6935293
• NM_001206927.2:c.863A>G

Variant summary

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

The NM_001206927.2(DNAH8):​c.863A>G​(p.Asn288Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,582,706 control chromosomes in the GnomAD database, including 1,721 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (176 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1545 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.66
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023658872).
• BP6: Variant 6-38737167-A-G is Benign according to our data. Variant chr6-38737167-A-G is described in ClinVar as Benign. ClinVar VariationId is 414419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.089 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.863A>G	p.Asn288Ser	missense	Exon 6 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.212A>G	p.Asn71Ser	missense	Exon 5 of 92	NP_001362.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.863A>G	p.Asn288Ser	missense	Exon 6 of 93	ENSP00000333363.7
	DNAH8	ENST00000359357.7	TSL:2	c.212A>G	p.Asn71Ser	missense	Exon 4 of 91	ENSP00000352312.3
	DNAH8	ENST00000449981.6	TSL:5	c.863A>G	p.Asn288Ser	missense	Exon 5 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6897 AN: 152180 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.0464

Gnomad EAS AF: 0.0956

Gnomad SAS AF: 0.0474

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0521

GnomAD2 exomes AF: 0.0425 AC: 9749 AN: 229310 AF XY: 0.0421

Gnomad AFR exome AF: 0.0326

Gnomad AMR exome AF: 0.0317

Gnomad ASJ exome AF: 0.0391

Gnomad EAS exome AF: 0.0641

Gnomad FIN exome AF: 0.0739

Gnomad NFE exome AF: 0.0386

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0417 AC: 59659 AN: 1430408 Hom.: 1545 Cov.: 30 AF XY: 0.0417 AC XY: 29628 AN XY: 711010

African (AFR) AF: 0.0369 AC: 1182 AN: 32018

American (AMR) AF: 0.0344 AC: 1335 AN: 38842

Ashkenazi Jewish (ASJ) AF: 0.0419 AC: 1068 AN: 25510

East Asian (EAS) AF: 0.117 AC: 4408 AN: 37796

South Asian (SAS) AF: 0.0402 AC: 3216 AN: 80018

European-Finnish (FIN) AF: 0.0724 AC: 3825 AN: 52832

Middle Eastern (MID) AF: 0.0820 AC: 466 AN: 5680

European-Non Finnish (NFE) AF: 0.0379 AC: 41619 AN: 1098612

Other (OTH) AF: 0.0430 AC: 2540 AN: 59100

GnomAD4 genome AF: 0.0453 AC: 6898 AN: 152298 Hom.: 176 Cov.: 32 AF XY: 0.0468 AC XY: 3488 AN XY: 74452

African (AFR) AF: 0.0378 AC: 1570 AN: 41584

American (AMR) AF: 0.0415 AC: 635 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 161 AN: 3472

East Asian (EAS) AF: 0.0960 AC: 498 AN: 5188

South Asian (SAS) AF: 0.0472 AC: 228 AN: 4828

European-Finnish (FIN) AF: 0.0759 AC: 804 AN: 10586

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0413 AC: 2810 AN: 68026

Other (OTH) AF: 0.0543 AC: 115 AN: 2116

Alfa AF: 0.0428 Hom.: 229

Bravo AF: 0.0425

TwinsUK AF: 0.0375 AC: 139

ALSPAC AF: 0.0345 AC: 133

ESP6500AA AF: 0.0343 AC: 151

ESP6500EA AF: 0.0407 AC: 350

ExAC AF: 0.0486 AC: 5907

Asia WGS AF: 0.0790 AC: 273 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.53	T
Polyphen		0.011	B
Vest4		0.056
MPC		0.11
ClinPred		0.0037	T
GERP RS		2.8
Varity_R		0.070
gMVP		0.47
Mutation Taster		=100/0	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: rs6935293; hg19: chr6-38704943; COSMIC: COSV59448622; COSMIC: COSV59448622;