chr6-38781273-A-T

Position:

chr6-38781273-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001206927.2(DNAH8):c.2159A>T(p.Asp720Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.92

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH8	NM_001206927.2 linkuse as main transcript	c.2159A>T	p.Asp720Val	missense_variant	16/93	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.2159A>T	p.Asp720Val	missense_variant	16/93	5	NM_001206927.2	ENSP00000333363.7	A0A075B6F3
DNAH8	ENST00000359357.7 linkuse as main transcript	c.1508A>T	p.Asp503Val	missense_variant	14/91	2		ENSP00000352312.3	Q96JB1-1
DNAH8	ENST00000449981.6 linkuse as main transcript	c.2159A>T	p.Asp720Val	missense_variant	15/82	5		ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251164

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.2159A>T (p.D720V) alteration is located in exon 16 (coding exon 15) of the DNAH8 gene. This alteration results from a A to T substitution at nucleotide position 2159, causing the aspartic acid (D) at amino acid position 720 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 720 of the DNAH8 protein (p.Asp720Val). This variant is present in population databases (rs138373981, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 525380). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.066

T;T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.47

T;T;T

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.1

.;.;M

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.7

.;D;D

REVEL

Benign

0.25

Sift

Benign

0.19

.;T;T

Polyphen

0.90

.;.;P

Vest4

0.72

MVP

0.82

MPC

0.23

ClinPred

0.13

GERP RS

5.6

Varity_R

0.62

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: -19

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