dbSNP rs185283741: DNAH8:p.Ala3823Val (chr6-38935602-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_001206927.2(DNAH8):c.11468C>T(p.Ala3823Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00058 in 1,611,272 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 2 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.83

Publications

3 publications found

Variant links:

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 links:

DNAH8-AS1 (HGNC:40188): (DNAH8 antisense RNA 1)

DNAH8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07509413).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000608 (887/1459166) while in subpopulation NFE AF = 0.000739 (821/1110808). AF 95% confidence interval is 0.000696. There are 2 homozygotes in GnomAdExome4. There are 395 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH8	NM_001206927.2	MANE Select	c.11468C>T	p.Ala3823Val	missense	Exon 77 of 93	NP_001193856.1	A0A075B6F3
DNAH8	NM_001371.4		c.10817C>T	p.Ala3606Val	missense	Exon 76 of 92	NP_001362.2	Q96JB1-1
DNAH8-AS1	NR_038401.1		n.160+691G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.11468C>T	p.Ala3823Val	missense	Exon 77 of 93	ENSP00000333363.7	A0A075B6F3
DNAH8	ENST00000359357.7	TSL:2	c.10817C>T	p.Ala3606Val	missense	Exon 75 of 91	ENSP00000352312.3	Q96JB1-1
DNAH8	ENST00000449981.6	TSL:5	c.11468C>T	p.Ala3823Val	missense	Exon 76 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000373

AC:

AN:

249318

AF XY:

0.000319

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000614

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000513

Gnomad NFE exome

AF:

0.000495

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000608

AC:

887

AN:

1459166

Hom.:

Cov.:

AF XY:

0.000544

AC XY:

395

AN XY:

725864

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33362

American (AMR)

AF:

0.000540

AC:

AN:

44446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85776

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

53124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000739

AC:

821

AN:

1110808

Other (OTH)

AF:

0.000365

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000316

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41494

American (AMR)

AF:

0.0000655

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000284

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000438

Hom.:

Bravo

AF:

0.000264

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000437

AC:

EpiCase

AF:

0.000437

EpiControl

AF:

0.000594

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (2)

not specified (1)

Spermatogenic failure 46 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.0086

MetaRNN

Benign

0.075

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

PhyloP100

1.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.3

REVEL

Benign

0.097

Sift

Benign

0.15

Polyphen

0.0070

Vest4

0.42

MVP

0.53

MPC

0.17

ClinPred

0.061

GERP RS

6.0

Varity_R

0.16

gMVP

0.27

Mutation Taster

=89/11

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over