NM_031427.4:c.4-15T>C

Variant names:

• chr14-73654832-T-C
• rs185924269
• NM_031427.4:c.4-15T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_031427.4(DNAL1):​c.4-15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,507,920 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (5 hom.)
• Consequence: DNAL1 NM_031427.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.877
• Publications: 0 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: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-73654832-T-C is Benign according to our data. Variant chr14-73654832-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195386.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAL1	NM_031427.4	MANE Select	c.4-15T>C		intron	N/A	NP_113615.2	Q4LDG9-1
	DNAL1	NM_001201366.2		c.-114-15T>C		intron	N/A	NP_001188295.1	Q4LDG9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAL1	ENST00000553645.7	TSL:1 MANE Select	c.4-15T>C		intron	N/A	ENSP00000452037.1	Q4LDG9-1
	DNAL1	ENST00000554871.5	TSL:1	c.-114-15T>C		intron	N/A	ENSP00000451834.1	Q4LDG9-3
	DNAL1	ENST00000893991.1		c.4-15T>C		intron	N/A	ENSP00000564050.1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 309 AN: 151704 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00365

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00271

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00211 AC: 247 AN: 117202 AF XY: 0.00210

Gnomad AFR exome AF: 0.000441

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.000726

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00332

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00227 AC: 3076 AN: 1356098 Hom.: 5 Cov.: 33 AF XY: 0.00222 AC XY: 1483 AN XY: 668586

African (AFR) AF: 0.000310 AC: 9 AN: 29058

American (AMR) AF: 0.00208 AC: 55 AN: 26404

Ashkenazi Jewish (ASJ) AF: 0.00100 AC: 24 AN: 23942

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35398

South Asian (SAS) AF: 0.00153 AC: 110 AN: 72046

European-Finnish (FIN) AF: 0.00403 AC: 172 AN: 42686

Middle Eastern (MID) AF: 0.000376 AC: 2 AN: 5314

European-Non Finnish (NFE) AF: 0.00244 AC: 2597 AN: 1065058

Other (OTH) AF: 0.00189 AC: 106 AN: 56192

GnomAD4 genome AF: 0.00204 AC: 309 AN: 151822 Hom.: 2 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74218

African (AFR) AF: 0.000386 AC: 16 AN: 41504

American (AMR) AF: 0.00197 AC: 30 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.00365 AC: 38 AN: 10408

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

European-Non Finnish (NFE) AF: 0.00271 AC: 184 AN: 67882

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00254 Hom.: 0

Bravo AF: 0.00176

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.36
DANN	Benign	0.50
PhyloP100		0.88
Mutation Taster		=100/0	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: rs185924269; hg19: chr14-74121535;