chr6-38923168-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001206927.2(DNAH8):c.10773C>G(p.Phe3591Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000448 in 1,613,450 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 3 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.41

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 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1579431).

BP6

Variant 6-38923168-C-G is Benign according to our data. Variant chr6-38923168-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 454538.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000465 (680/1461334) while in subpopulation AMR AF = 0.00163 (73/44686). AF 95% confidence interval is 0.00133. There are 3 homozygotes in GnomAdExome4. There are 306 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2 link	c.10773C>G	p.Phe3591Leu	missense_variant	Exon 72 of 93	ENST00000327475.11	NP_001193856.1	Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH8	ENST00000327475.11 link	c.10773C>G	p.Phe3591Leu	missense_variant	Exon 72 of 93	5	NM_001206927.2	ENSP00000333363.7		A0A075B6F3

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000474

AC:

119

AN:

250942

AF XY:

0.000391

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000467

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000465

AC:

680

AN:

1461334

Hom.:

Cov.:

AF XY:

0.000421

AC XY:

306

AN XY:

726962

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33452

American (AMR)

AF:

0.00163

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000517

AC:

575

AN:

1111706

Other (OTH)

AF:

0.000513

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000283

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41426

American (AMR)

AF:

0.000328

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000309

Hom.:

Bravo

AF:

0.000332

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000535

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 27, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported with a second DNAH8 variant on the opposite allele (in trans) in a patient with dextrocardia, atrioventricular septal defect, asplenia, and failure to thrive in published literature (Reuter et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32037394) -

Primary ciliary dyskinesia

Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;D;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.069

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.6

.;.;L

PhyloP100

1.4

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.8

.;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.023

.;D;D

Polyphen

1.0

.;.;D

Vest4

0.68

MutPred

0.61

.;.;Loss of methylation at K3375 (P = 0.0339);

MVP

0.75

MPC

0.35

ClinPred

0.13

GERP RS

3.5

Varity_R

0.49

gMVP

0.55

Mutation Taster

=70/30

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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chr6-38923168-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over