chr14-73654843-A-T

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

2
Splicing: ADA: 0.00003782
2

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

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 HGVSp Effect Exon rank MANE Protein UniProt
DNAL1NM_031427.4 linkc.4-4A>T splice_region_variant, intron_variant Intron 1 of 7 ENST00000553645.7 NP_113615.2 Q4LDG9-1
DNAL1NM_001201366.2 linkc.-114-4A>T splice_region_variant, intron_variant Intron 2 of 8 NP_001188295.1 Q4LDG9-3
DNAL1XM_017021679.3 linkc.-114-4A>T splice_region_variant, intron_variant Intron 2 of 8 XP_016877168.1 Q4LDG9-3
DNAL1XM_024449715.2 linkc.-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
DNAL1ENST00000553645.7 linkc.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:
3
AN:
148814
Hom.:
0
Cov.:
31
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.:
0
Cov.:
33
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:
43
AN:
24514
American (AMR)
AF:
0.00616
AC:
115
AN:
18670
Ashkenazi Jewish (ASJ)
AF:
0.00250
AC:
48
AN:
19176
East Asian (EAS)
AF:
0.00321
AC:
89
AN:
27694
South Asian (SAS)
AF:
0.00362
AC:
205
AN:
56618
European-Finnish (FIN)
AF:
0.00259
AC:
90
AN:
34712
Middle Eastern (MID)
AF:
0.00128
AC:
6
AN:
4686
European-Non Finnish (NFE)
AF:
0.000934
AC:
891
AN:
954370
Other (OTH)
AF:
0.00182
AC:
87
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
0
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
0
20
40
60
80
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:
3
AN:
148908
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
1
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:
1
AN:
40514
American (AMR)
AF:
0.000133
AC:
2
AN:
15034
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3460
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5150
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4752
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9388
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67330
Other (OTH)
AF:
0.00
AC:
0
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
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00436
Hom.:
0

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
DANN
Benign
0.66
PhyloP100
0.020
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs576147534; hg19: chr14-74121546; COSMIC: COSV60726634; COSMIC: COSV60726634; API