Genetic Variant DNAH6:p.Arg3292Ser (chr2-84722706-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001370.2(DNAH6):c.9874C>A(p.Arg3292Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3292C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNAH6
NM_001370.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.28

Publications

2 publications found

Variant links:

Genes affected

DNAH6 (HGNC:2951): (dynein axonemal heavy chain 6) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Mutations in this gene may cause primary ciliary dyskinesia (PCD) as well as heterotaxy. [provided by RefSeq, Jun 2016]

DNAH6 Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center

DNAH6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH6	NM_001370.2 link	c.9874C>A	p.Arg3292Ser	missense_variant	Exon 60 of 77	ENST00000389394.8	NP_001361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH6	ENST00000389394.8 link	c.9874C>A	p.Arg3292Ser	missense_variant	Exon 60 of 77	5	NM_001370.2	ENSP00000374045.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1396152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688730

African (AFR)

AF:

0.00

AC:

AN:

31366

American (AMR)

AF:

0.00

AC:

AN:

34610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25088

East Asian (EAS)

AF:

0.00

AC:

AN:

35674

South Asian (SAS)

AF:

0.00

AC:

AN:

78740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077858

Other (OTH)

AF:

0.00

AC:

AN:

57870

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.074

T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.92

D;.

M_CAP

Uncertain

0.091

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-0.32

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

1.3

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.019

D;D

Polyphen

0.83

P;P

Vest4

0.67

MutPred

0.49

Loss of MoRF binding (P = 0.0284);Loss of MoRF binding (P = 0.0284);

MVP

0.51

MPC

0.21

ClinPred

0.97

GERP RS

4.8

Varity_R

0.43

gMVP

0.75

Mutation Taster

=55/45

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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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