Genetic Variant DNAL1:c.4-4A>T (chr14-73654843-A-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_031427.4(DNAL1):c.4-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,188,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DNAL1
NM_031427.4 splice_region, intron

Scores

Splicing: ADA: 0.00003782

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0200

Publications

2 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 14-73654843-A-T is Benign according to our data. Variant chr14-73654843-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 414000.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DNAL1	NM_031427.4 link	c.4-4A>T	splice_region_variant, intron_variant	Intron 1 of 7	ENST00000553645.7	NP_113615.2	Q4LDG9-1
DNAL1	NM_001201366.2 link	c.-114-4A>T	splice_region_variant, intron_variant	Intron 2 of 8		NP_001188295.1	Q4LDG9-3
DNAL1	XM_017021679.3 link	c.-114-4A>T	splice_region_variant, intron_variant	Intron 2 of 8		XP_016877168.1	Q4LDG9-3
DNAL1	XM_024449715.2 link	c.-114-4A>T	splice_region_variant, intron_variant	Intron 2 of 8		XP_024305483.1

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.0000202

AC:

AN:

148814

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

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

GnomAD2 exomes

AF:

0.00367

AC:

338

AN:

92032

AF XY:

0.00362

show subpopulations

Gnomad AFR exome

AF:

0.00300

Gnomad AMR exome

AF:

0.00963

Gnomad ASJ exome

AF:

0.00177

Gnomad EAS exome

AF:

0.00598

Gnomad FIN exome

AF:

0.00261

Gnomad NFE exome

AF:

0.00260

Gnomad OTH exome

AF:

0.00429

GnomAD4 exome

AF:

0.00132

AC:

1574

AN:

1188308

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

811

AN XY:

582942

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00175

AC:

AN:

24514

American (AMR)

AF:

0.00616

AC:

115

AN:

18670

Ashkenazi Jewish (ASJ)

AF:

0.00250

AC:

AN:

19176

East Asian (EAS)

AF:

0.00321

AC:

AN:

27694

South Asian (SAS)

AF:

0.00362

AC:

205

AN:

56618

European-Finnish (FIN)

AF:

0.00259

AC:

AN:

34712

Middle Eastern (MID)

AF:

0.00128

AC:

AN:

4686

European-Non Finnish (NFE)

AF:

0.000934

AC:

891

AN:

954370

Other (OTH)

AF:

0.00182

AC:

AN:

47868

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.228

Heterozygous variant carriers

200

400

600

800

1000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000201

AC:

AN:

148908

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72566

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000247

AC:

AN:

40514

American (AMR)

AF:

0.000133

AC:

AN:

15034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67330

Other (OTH)

AF:

0.00

AC:

AN:

2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.003801), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00436

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 16

Benign:1

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.45

(source)

DANN

Benign

0.66

PhyloP100

0.020

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000038

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over