Genetic Variant DNAH8:p.Leu1461Leu (chr6-38837959-G-A) – 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.4383G>A(p.Leu1461Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,612,692 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 14 hom. )

Consequence

DNAH8
NM_001206927.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.141

Publications

5 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 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

DNAH8 links:

Genome browser will be placed here

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=-0.53).

BP6

Variant 6-38837959-G-A is Benign according to our data. Variant chr6-38837959-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 224918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.141 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00311 (473/152274) while in subpopulation AMR AF = 0.00981 (150/15296). AF 95% confidence interval is 0.00853. There are 2 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH8	NM_001206927.2	MANE Select	c.4383G>A	p.Leu1461Leu	synonymous	Exon 33 of 93	NP_001193856.1
	DNAH8	NM_001371.4		c.3732G>A	p.Leu1244Leu	synonymous	Exon 32 of 92	NP_001362.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.4383G>A	p.Leu1461Leu	synonymous	Exon 33 of 93	ENSP00000333363.7
DNAH8	ENST00000359357.7	TSL:2	c.3732G>A	p.Leu1244Leu	synonymous	Exon 31 of 91	ENSP00000352312.3
DNAH8	ENST00000449981.6	TSL:5	c.4383G>A	p.Leu1461Leu	synonymous	Exon 32 of 82	ENSP00000415331.2

Frequencies

GnomAD3 genomes

AF:

0.00311

AC:

473

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00982

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00375

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00327

AC:

820

AN:

250674

AF XY:

0.00336

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00463

Gnomad OTH exome

AF:

0.00426

GnomAD4 exome

AF:

0.00359

AC:

5236

AN:

1460418

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

2581

AN XY:

726564

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33440

American (AMR)

AF:

0.00502

AC:

224

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.00647

AC:

169

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.000499

AC:

AN:

86134

European-Finnish (FIN)

AF:

0.000937

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00409

AC:

4540

AN:

1111080

Other (OTH)

AF:

0.00322

AC:

194

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

216

433

649

866

1082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00311

AC:

473

AN:

152274

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

208

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000578

AC:

AN:

41546

American (AMR)

AF:

0.00981

AC:

150

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00375

AC:

255

AN:

68024

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00344

Hom.:

Bravo

AF:

0.00355

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00426

EpiControl

AF:

0.00463

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAH8: BP4, BP7, BS2

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

2.4

(source)

DANN

Benign

0.57

PhyloP100

-0.14

Mutation Taster

=99/1

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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over