Variant 2-84525590-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001370.2(DNAH6):c.251A>T(p.His84Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,395,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

DNAH6
NM_001370.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21

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 links:

DNAH6 (HGNC:):

DNAH6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNAH6. . Gene score misZ 3.5535 (greater than the threshold 3.09). Trascript score misZ 3.4022 (greater than threshold 3.09). GenCC has associacion of gene with male infertility with azoospermia or oligozoospermia due to single gene mutation.

BP4

Computational evidence support a benign effect (MetaRNN=0.13190809).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH6	NM_001370.2 linkuse as main transcript	c.251A>T	p.His84Leu	missense_variant	3/77	ENST00000389394.8	NP_001361.1	Q9C0G6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAH6	ENST00000389394.8 linkuse as main transcript	c.251A>T	p.His84Leu	missense_variant	3/77	5	NM_001370.2	ENSP00000374045.3	Q9C0G6-1
DNAH6	ENST00000494025.1 linkuse as main transcript	n.229+7539A>T		intron_variant		1
DNAH6	ENST00000468661.1 linkuse as main transcript	n.306A>T		non_coding_transcript_exon_variant	3/4	4
DNAH6	ENST00000476689.5 linkuse as main transcript	n.388A>T		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1395274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688054

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

9.28e-7

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.251A>T (p.H84L) alteration is located in exon 3 (coding exon 2) of the DNAH6 gene. This alteration results from a A to T substitution at nucleotide position 251, causing the histidine (H) at amino acid position 84 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.035

T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.073

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.61

T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.0

D;D

REVEL

Benign

0.082

Sift

Uncertain

0.014

D;D

Polyphen

0.037

B;B

Vest4

0.43

MVP

0.25

MPC

0.12

ClinPred

0.44

GERP RS

4.3

Varity_R

0.19

gMVP

0.28

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