Genetic Variant DNAH8:p.Leu3926Leu (chr6-38938186-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001206927.2(DNAH8):c.11776T>C(p.Leu3926Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,613,890 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 8 hom. )

Consequence

DNAH8
NM_001206927.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.27

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 6-38938186-T-C is Benign according to our data. Variant chr6-38938186-T-C is described in ClinVar as Benign. ClinVar VariationId is 414392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.27 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00168 (256/152308) while in subpopulation NFE AF = 0.00223 (152/68034). AF 95% confidence interval is 0.00194. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 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.11776T>C	p.Leu3926Leu	synonymous	Exon 78 of 93	NP_001193856.1	A0A075B6F3
DNAH8	NM_001371.4		c.11125T>C	p.Leu3709Leu	synonymous	Exon 77 of 92	NP_001362.2	Q96JB1-1
DNAH8-AS1	NR_038401.1		n.61-1794A>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.11776T>C	p.Leu3926Leu	synonymous	Exon 78 of 93	ENSP00000333363.7	A0A075B6F3
DNAH8	ENST00000359357.7	TSL:2	c.11125T>C	p.Leu3709Leu	synonymous	Exon 76 of 91	ENSP00000352312.3	Q96JB1-1
DNAH8	ENST00000449981.6	TSL:5	c.11776T>C	p.Leu3926Leu	synonymous	Exon 77 of 82	ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00223

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00169

AC:

423

AN:

250636

AF XY:

0.00167

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00229

Gnomad NFE exome

AF:

0.00231

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00226

AC:

3296

AN:

1461582

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

1570

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33478

American (AMR)

AF:

0.00192

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00244

AC:

130

AN:

53188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00263

AC:

2920

AN:

1111950

Other (OTH)

AF:

0.00192

AC:

116

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

170

339

509

678

848

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00168

AC:

256

AN:

152308

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41576

American (AMR)

AF:

0.00216

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00386

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00223

AC:

152

AN:

68034

Other (OTH)

AF:

0.00237

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.00174

Hom.:

Bravo

AF:

0.00148

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00229

EpiControl

AF:

0.00231

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (1)

Spermatogenic failure 46 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.3

(source)

DANN

Benign

0.80

PhyloP100

2.3

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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