chr6-38734588-G-A

Position:

chr6-38734588-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001206927.2(DNAH8):c.725G>A(p.Arg242His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,613,482 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 1 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0670

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.009264529).

BP6

Variant 6-38734588-G-A is Benign according to our data. Variant chr6-38734588-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238655.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000276 (42/152274) while in subpopulation EAS AF= 0.00308 (16/5188). AF 95% confidence interval is 0.00193. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH8	NM_001206927.2 linkuse as main transcript	c.725G>A	p.Arg242His	missense_variant	5/93	ENST00000327475.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH8	ENST00000327475.11 linkuse as main transcript	c.725G>A	p.Arg242His	missense_variant	5/93	5	NM_001206927.2	P2
DNAH8	ENST00000359357.7 linkuse as main transcript	c.74G>A	p.Arg25His	missense_variant	3/91	2		A2	Q96JB1-1
DNAH8	ENST00000449981.6 linkuse as main transcript	c.725G>A	p.Arg242His	missense_variant	4/82	5

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000438

AC:

110

AN:

251274

Hom.:

AF XY:

0.000427

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00370

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000296

AC:

432

AN:

1461208

Hom.:

Cov.:

AF XY:

0.000279

AC XY:

203

AN XY:

726914

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00255

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000227

Gnomad4 OTH exome

AF:

0.000895

GnomAD4 genome

AF:

0.000276

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00308

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000399

Hom.:

Bravo

AF:

0.000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000461

AC:

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Primary ciliary dyskinesia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

- -

Spermatogenic failure 46

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

T;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.25

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0093

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.74

.;.;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.63

.;N;N

REVEL

Benign

0.095

Sift

Benign

0.13

.;T;T

Polyphen

0.66

.;.;P

Vest4

0.18

MVP

0.64

MPC

0.15

ClinPred

0.0098

GERP RS

-1.7

Varity_R

0.047

gMVP

0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over