NM_031427.4:c.415C>G

Variant names:

• chr14-73689398-C-G
• rs141873943
• NM_031427.4:c.415C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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. 13/22 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:3 B:3
• Conservation: PhyloP100: 0.269
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 178765.
• 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031427.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAL1	NM_031427.4	MANE Select	c.415C>G	p.Leu139Val	missense	Exon 7 of 8	NP_113615.2
	DNAL1	NM_001201366.2		c.298C>G	p.Leu100Val	missense	Exon 8 of 9	NP_001188295.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAL1	ENST00000553645.7	TSL:1 MANE Select	c.415C>G	p.Leu139Val	missense	Exon 7 of 8	ENSP00000452037.1
	DNAL1	ENST00000554871.5	TSL:1	c.298C>G	p.Leu100Val	missense	Exon 8 of 9	ENSP00000451834.1
	DNAL1	ENST00000555631.6	TSL:4	c.298C>G	p.Leu100Val	missense	Exon 8 of 8	ENSP00000451547.2

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

GnomAD2 exomes AF: 0.00170 AC: 272 AN: 160362 AF XY: 0.00167

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 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

African (AFR) AF: 0.000505 AC: 16 AN: 31652

American (AMR) AF: 0.00428 AC: 153 AN: 35732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35862

South Asian (SAS) AF: 0.0000631 AC: 5 AN: 79250

European-Finnish (FIN) AF: 0.0000605 AC: 3 AN: 49626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00328 AC: 3538 AN: 1079566

Other (OTH) AF: 0.00277 AC: 161 AN: 58174

GnomAD4 genome AF: 0.00194 AC: 296 AN: 152288 Hom.: 0 Cov.: 30 AF XY: 0.00187 AC XY: 139 AN XY: 74456

African (AFR) AF: 0.000577 AC: 24 AN: 41568

American (AMR) AF: 0.00471 AC: 72 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 68036

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	2	not specified (2)
-	1	1	Primary ciliary dyskinesia 16 (2)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.27
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.24
Sift	Benign	0.11	T
Sift4G	Benign	0.098	T
Polyphen		0.24	B
Vest4		0.35
MVP		0.42
MPC		0.45
ClinPred		0.046	T
GERP RS		1.4
Varity_R		0.15
gMVP		0.53
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs141873943; hg19: chr14-74156101;