dbSNP rs1555403597: DNAL1:c.533-2A>G (chr14-73695900-A-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_031427.4(DNAL1):c.533-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNAL1
NM_031427.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.98

Publications

0 publications found

Variant links:

Genes affected

DNAL1 (HGNC:23247): (dynein axonemal light chain 1) This gene encodes an axonemal dynein light chain which functions as a component of the outer dynein arms complex. This complex acts as the molecular motor that provides the force to move cilia in an ATP-dependent manner. The encoded protein is expressed in tissues with motile cilia or flagella and may be involved in the movement of sperm flagella. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jan 2011]

DNAL1 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 16
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DNAL1	NM_031427.4 link	c.533-2A>G	splice_acceptor_variant, intron_variant	Intron 7 of 7	ENST00000553645.7	NP_113615.2	Q4LDG9-1
DNAL1	NM_001201366.2 link	c.416-2A>G	splice_acceptor_variant, intron_variant	Intron 8 of 8		NP_001188295.1	Q4LDG9-3
DNAL1	XM_017021679.3 link	c.416-2A>G	splice_acceptor_variant, intron_variant	Intron 8 of 8		XP_016877168.1	Q4LDG9-3
DNAL1	XM_024449715.2 link	c.416-2A>G	splice_acceptor_variant, intron_variant	Intron 8 of 8		XP_024305483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAL1	ENST00000553645.7 link	c.533-2A>G		splice_acceptor_variant, intron_variant	Intron 7 of 7	1	NM_031427.4	ENSP00000452037.1		Q4LDG9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1425066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705898

African (AFR)

AF:

0.00

AC:

AN:

32510

American (AMR)

AF:

0.00

AC:

AN:

39430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25468

East Asian (EAS)

AF:

0.00

AC:

AN:

38550

South Asian (SAS)

AF:

0.00

AC:

AN:

80802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092148

Other (OTH)

AF:

0.00

AC:

AN:

58988

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 16

Uncertain:1

Apr 29, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in DNAL1 cause disease. Therefore, this variant has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DNAL1-related disease. This sequence change affects an acceptor splice site in intron 7 of the DNAL1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.94

PhyloP100

6.0

GERP RS

5.8

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.56

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.56

Position offset: 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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over