rs141873943

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_031427.4(DNAL1):c.415C>G(p.Leu139Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,553,030 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0028 ( 9 hom. )

Consequence

DNAL1
NM_031427.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.269

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007347524).

BP6

Variant 14-73689398-C-G is Benign according to our data. Variant chr14-73689398-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178765.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00194 (296/152288) while in subpopulation AMR AF= 0.00471 (72/15286). AF 95% confidence interval is 0.00384. There are 0 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAL1	NM_031427.4 link	c.415C>G	p.Leu139Val	missense_variant	7/8	ENST00000553645.7	NP_113615.2	Q4LDG9-1
DNAL1	NM_001201366.2 link	c.298C>G	p.Leu100Val	missense_variant	8/9		NP_001188295.1	Q4LDG9-3
DNAL1	XM_017021679.3 link	c.298C>G	p.Leu100Val	missense_variant	8/9		XP_016877168.1	Q4LDG9-3
DNAL1	XM_024449715.2 link	c.298C>G	p.Leu100Val	missense_variant	8/9		XP_024305483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAL1	ENST00000553645.7 link	c.415C>G	p.Leu139Val	missense_variant	7/8	1	NM_031427.4	ENSP00000452037.1		Q4LDG9-1

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

296

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00472

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00170

AC:

272

AN:

160362

Hom.:

AF XY:

0.00167

AC XY:

141

AN XY:

84302

show subpopulations

Gnomad AFR exome

AF:

0.000355

Gnomad AMR exome

AF:

0.00339

Gnomad ASJ exome

AF:

0.000233

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00279

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.00277

AC:

3876

AN:

1400742

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

1805

AN XY:

690976

show subpopulations

Gnomad4 AFR exome

AF:

0.000505

Gnomad4 AMR exome

AF:

0.00428

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000631

Gnomad4 FIN exome

AF:

0.0000605

Gnomad4 NFE exome

AF:

0.00328

Gnomad4 OTH exome

AF:

0.00277

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152288

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

139

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00471

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00163

Hom.:

Bravo

AF:

0.00268

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000541

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.000910

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 18, 2023	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 05, 2014	- -

Primary ciliary dyskinesia 16

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	The DNAL1 c.415C>G; p.Leu139Val variant (rs141873943; ClinVar Variation ID: 178765) has been observed in a cohort of patients referred for Bronchiectasis, but no additional evidence of causality was provided (Olm 2019). This variant is found in the Latino population with an allele frequency of 0.34% (88/25652 alleles) in the Genome Aggregation Database. The leucine at codon 139 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.241). Due to limited information, the clinical significance of the p.Leu139Val variant is uncertain at this time. References: Olm MAK et al. Severe pulmonary disease in an adult primary ciliary dyskinesia population in Brazil. Sci Rep. 2019 Jun 18;9(1):8693. PMID: 31213628 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Leu100Val in exon 8 of DNAL1: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (30/8054) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs141873943). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.060

.;.;T;.;.;.;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.46

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.0073

T;T;T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.1

.;.;M;.;.;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.0

N;.;N;N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.11

T;.;T;T;T;T;T

Sift4G

Benign

0.098

T;T;T;T;T;T;T

Polyphen

0.24

.;.;B;.;.;.;.

Vest4

0.35, 0.33, 0.35, 0.34

MVP

0.42

MPC

0.45

ClinPred

0.046

GERP RS

1.4

Varity_R

0.15

gMVP

0.53

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