rs61757218

Positions:

chr6-38938181-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001206927.2(DNAH8):c.11771C>T(p.Thr3924Met) variant causes a missense change. The variant allele was found at a frequency of 0.00617 in 1,613,926 control chromosomes in the GnomAD database, including 38 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 0.0066 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0061 ( 31 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:4

Conservation

PhyloP100: 6.16

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 (HGNC:):

DNAH8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014879525).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00663 (1009/152274) while in subpopulation AFR AF= 0.00917 (381/41552). AF 95% confidence interval is 0.00841. There are 7 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2 linkuse as main transcript	c.11771C>T	p.Thr3924Met	missense_variant	78/93	ENST00000327475.11	NP_001193856.1	Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAH8	ENST00000327475.11 linkuse as main transcript	c.11771C>T	p.Thr3924Met	missense_variant	78/93	5	NM_001206927.2	ENSP00000333363.7	A0A075B6F3
DNAH8	ENST00000359357.7 linkuse as main transcript	c.11120C>T	p.Thr3707Met	missense_variant	76/91	2		ENSP00000352312.3	Q96JB1-1
DNAH8	ENST00000449981.6 linkuse as main transcript	c.11771C>T	p.Thr3924Met	missense_variant	77/82	5		ENSP00000415331.2	H0Y7V4
DNAH8-AS1	ENST00000416948.1 linkuse as main transcript	n.53-1789G>A		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00663

AC:

1009

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00922

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00832

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00661

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00518

AC:

1298

AN:

250738

Hom.:

AF XY:

0.00504

AC XY:

683

AN XY:

135550

show subpopulations

Gnomad AFR exome

AF:

0.00855

Gnomad AMR exome

AF:

0.00535

Gnomad ASJ exome

AF:

0.00367

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.00159

Gnomad NFE exome

AF:

0.00705

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00613

AC:

8956

AN:

1461652

Hom.:

Cov.:

AF XY:

0.00599

AC XY:

4352

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00998

Gnomad4 AMR exome

AF:

0.00523

Gnomad4 ASJ exome

AF:

0.00432

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00204

Gnomad4 FIN exome

AF:

0.00184

Gnomad4 NFE exome

AF:

0.00681

Gnomad4 OTH exome

AF:

0.00664

GnomAD4 genome

AF:

0.00663

AC:

1009

AN:

152274

Hom.:

Cov.:

AF XY:

0.00653

AC XY:

486

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00917

Gnomad4 AMR

AF:

0.00831

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00661

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00605

Hom.:

Bravo

AF:

0.00707

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.00663

AC:

ExAC

AF:

0.00510

AC:

619

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00676

EpiControl

AF:

0.00699

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2023	Identified in the heterozygous state in a patient with transposition of the great arteries and abnormal ciliary motion (Zahid et al., 2018); 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: 32619401, 29444099) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	DNAH8: BS2 -

Spermatogenic failure 46

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 13, 2020

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Candidate PCD gene, but frequency is high -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;T;T

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D;D

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.075

MutationAssessor

Pathogenic

4.1

.;.;H

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.9

.;D;D

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

.;D;D

Polyphen

1.0

.;.;D

Vest4

0.79

MVP

0.87

MPC

0.58

ClinPred

0.084

GERP RS

5.6

Varity_R

0.64

gMVP

0.68

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