chr6-39012305-A-G

Variant names:

• chr6-39012305-A-G
• rs10484847
• NM_001206927.2:c.13462A>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.13462A>G​(p.Ile4488Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,611,998 control chromosomes in the GnomAD database, including 20,859 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4488L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (1833 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19026 hom.)
• Consequence: DNAH8 NM_001206927.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.232
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017467737).
• BP6: Variant 6-39012305-A-G is Benign according to our data. Variant chr6-39012305-A-G is described in ClinVar as Benign. ClinVar VariationId is 257630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 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.13462A>G	p.Ile4488Val	missense	Exon 90 of 93	NP_001193856.1	A0A075B6F3
	DNAH8	NM_001371.4		c.12811A>G	p.Ile4271Val	missense	Exon 89 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.13462A>G	p.Ile4488Val	missense	Exon 90 of 93	ENSP00000333363.7	A0A075B6F3
	DNAH8	ENST00000359357.7	TSL:2	c.12811A>G	p.Ile4271Val	missense	Exon 88 of 91	ENSP00000352312.3	Q96JB1-1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22541 AN: 152148 Hom.: 1834 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.00365

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.175

GnomAD2 exomes AF: 0.143 AC: 35830 AN: 250908 AF XY: 0.146

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.00310

Gnomad FIN exome AF: 0.110

Gnomad NFE exome AF: 0.171

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.156 AC: 227704 AN: 1459732 Hom.: 19026 Cov.: 31 AF XY: 0.156 AC XY: 113371 AN XY: 726130

African (AFR) AF: 0.138 AC: 4608 AN: 33438

American (AMR) AF: 0.116 AC: 5182 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 6906 AN: 26064

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39676

South Asian (SAS) AF: 0.136 AC: 11736 AN: 86094

European-Finnish (FIN) AF: 0.110 AC: 5866 AN: 53372

Middle Eastern (MID) AF: 0.212 AC: 1221 AN: 5754

European-Non Finnish (NFE) AF: 0.164 AC: 182487 AN: 1110370

Other (OTH) AF: 0.159 AC: 9616 AN: 60298

GnomAD4 genome AF: 0.148 AC: 22537 AN: 152266 Hom.: 1833 Cov.: 32 AF XY: 0.144 AC XY: 10711 AN XY: 74466

African (AFR) AF: 0.138 AC: 5756 AN: 41564

American (AMR) AF: 0.140 AC: 2146 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 979 AN: 3470

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5188

South Asian (SAS) AF: 0.120 AC: 578 AN: 4818

European-Finnish (FIN) AF: 0.0960 AC: 1018 AN: 10604

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11513 AN: 68002

Other (OTH) AF: 0.171 AC: 362 AN: 2112

Alfa AF: 0.162 Hom.: 6456

Bravo AF: 0.154

TwinsUK AF: 0.158 AC: 585

ALSPAC AF: 0.170 AC: 655

ESP6500AA AF: 0.146 AC: 642

ESP6500EA AF: 0.180 AC: 1549

ExAC AF: 0.146 AC: 17690

Asia WGS AF: 0.0600 AC: 210 AN: 3478

EpiCase AF: 0.176

EpiControl AF: 0.172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.9
DANN	Benign	0.94
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.42	N
PhyloP100		0.23
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.037
Sift	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.045
MPC		0.10
ClinPred		0.0015	T
GERP RS		2.5
Varity_R		0.056
gMVP		0.21
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: rs10484847; hg19: chr6-38980081; COSMIC: COSV59446520;