rs141873943

Positions:

• chr14-73689398-C-G
• chr14-73689398-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.269

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]

ACMG classification

Verdict is Benign. Variant got -9 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=2, Likely_benign=3}.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAL1	NM_031427.4	c.415C>G	p.Leu139Val	missense_variant	7/8	ENST00000553645.7
DNAL1	NM_001201366.2	c.298C>G	p.Leu100Val	missense_variant	8/9
DNAL1	XM_017021679.3	c.298C>G	p.Leu100Val	missense_variant	8/9
DNAL1	XM_024449715.2	c.298C>G	p.Leu100Val	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAL1	ENST00000553645.7	c.415C>G	p.Leu139Val	missense_variant	7/8	1	NM_031427.4	P1

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 152170 Hom.: 0 Cov.: 30

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.: 0 AF XY: 0.00167 AC XY: 141 AN XY: 84302

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.: 9 Cov.: 31 AF XY: 0.00261 AC XY: 1805 AN XY: 690976

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.: 0 Cov.: 30 AF XY: 0.00187 AC XY: 139 AN XY: 74456

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.: 0

Bravo AF: 0.00268

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000541 AC: 2

ESP6500EA AF: 0.00372 AC: 30

ExAC AF: 0.000910 AC: 96

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 16 Uncertain:1 Benign:1

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 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -

not specified Benign:2

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). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 05, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0073	T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
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	T
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

Other links and lift over

dbSNP: rs141873943; hg19: chr14-74156101;