Genetic Variant DNAH8:p.Leu194Phe (chr6-38729958-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001206927.2(DNAH8):c.582G>C(p.Leu194Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.484

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 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06721467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2 link	c.582G>C	p.Leu194Phe	missense_variant	Exon 4 of 93	ENST00000327475.11	NP_001193856.1	Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH8	ENST00000327475.11 link	c.582G>C	p.Leu194Phe	missense_variant	Exon 4 of 93	5	NM_001206927.2	ENSP00000333363.7	A0A075B6F3
DNAH8	ENST00000373278.8 link	c.582G>C	p.Leu194Phe	missense_variant	Exon 4 of 5	1		ENSP00000362375.4	Q8IU65
DNAH8	ENST00000449981.6 link	c.582G>C	p.Leu194Phe	missense_variant	Exon 3 of 82	5		ENSP00000415331.2	H0Y7V4
DNAH8	ENST00000359357.7 link	c.-41-4516G>C		intron_variant	Intron 2 of 90	2		ENSP00000352312.3	Q96JB1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443002

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33094

American (AMR)

AF:

0.00

AC:

AN:

44056

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25950

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39442

South Asian (SAS)

AF:

0.00

AC:

AN:

84554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098288

Other (OTH)

AF:

0.00

AC:

AN:

59752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.0024

T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.55

T;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.067

T;T;T

MetaSVM

Benign

-0.96

PhyloP100

-0.48

PrimateAI

Benign

0.41

PROVEAN

Benign

2.1

.;N;N

REVEL

Benign

0.062

Sift

Benign

0.61

.;T;T

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

0.20

.;B;.

Vest4

0.17

MutPred

0.53

Loss of ubiquitination at K192 (P = 0.1268);Loss of ubiquitination at K192 (P = 0.1268);Loss of ubiquitination at K192 (P = 0.1268);

MVP

0.040

ClinPred

0.059

GERP RS

-2.6

gMVP

0.24

Mutation Taster

=76/24

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over