rs375668014

Variant names:

• chr6-38775941-A-G
• rs375668014
• NM_001206927.2:c.1952A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001206927.2(DNAH8):​c.1952A>G​(p.Asn651Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,608,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.273
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045035064).

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.1952A>G	p.Asn651Ser	missense	Exon 13 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.1301A>G	p.Asn434Ser	missense	Exon 12 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.1952A>G	p.Asn651Ser	missense	Exon 13 of 93	ENSP00000333363.7
	DNAH8	ENST00000359357.7	TSL:2	c.1301A>G	p.Asn434Ser	missense	Exon 11 of 91	ENSP00000352312.3
	DNAH8	ENST00000449981.6	TSL:5	c.1952A>G	p.Asn651Ser	missense	Exon 12 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000227 AC: 57 AN: 250576 AF XY: 0.000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000318

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000137 AC: 200 AN: 1456182 Hom.: 0 Cov.: 28 AF XY: 0.000131 AC XY: 95 AN XY: 724778

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.000246 AC: 11 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39500

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.000149 AC: 165 AN: 1107210

Other (OTH) AF: 0.0000997 AC: 6 AN: 60176

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74374

African (AFR) AF: 0.0000482 AC: 2 AN: 41470

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68048

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	0.052
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.9
DANN	Benign	0.70
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.32	N
PhyloP100		0.27
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.33
MPC		0.096
ClinPred		0.015	T
GERP RS		0.67
Varity_R		0.051
gMVP		0.10
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs375668014; hg19: chr6-38743717;