14-73654828-CTTTTTTTTT-CTTTTTTTTTT

Variant names:

• chr14-73654828-C-CT
• rs753404083
• NM_031427.4:c.4-5dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_031427.4(DNAL1):​c.4-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 1,272,226 control chromosomes in the GnomAD database, including 5 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 31)
  • Exomes 𝑓: 0.035 (0 hom.)
• Consequence: DNAL1 NM_031427.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.663
• Publications: 1 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00535 (760/142128) while in subpopulation AFR AF = 0.0166 (648/38950). AF 95% confidence interval is 0.0156. There are 5 homozygotes in GnomAd4. There are 352 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.4-5dupT		splice_region intron	N/A	NP_113615.2	Q4LDG9-1
	DNAL1	NM_001201366.2		c.-114-5dupT		splice_region 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.4-19_4-18insT		intron	N/A	ENSP00000452037.1	Q4LDG9-1
	DNAL1	ENST00000554871.5	TSL:1	c.-114-19_-114-18insT		intron	N/A	ENSP00000451834.1	Q4LDG9-3
	DNAL1	ENST00000893991.1		c.4-19_4-18insT		intron	N/A	ENSP00000564050.1

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 761 AN: 142114 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00200

Gnomad ASJ AF: 0.00599

Gnomad EAS AF: 0.00161

Gnomad SAS AF: 0.000222

Gnomad FIN AF: 0.00261

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.0397 AC: 2951 AN: 74314 AF XY: 0.0373

Gnomad AFR exome AF: 0.0582

Gnomad AMR exome AF: 0.0522

Gnomad ASJ exome AF: 0.0388

Gnomad EAS exome AF: 0.0530

Gnomad FIN exome AF: 0.0371

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0411

GnomAD4 exome AF: 0.0350 AC: 39574 AN: 1130098 Hom.: 0 Cov.: 0 AF XY: 0.0349 AC XY: 19526 AN XY: 560134

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0489 AC: 1200 AN: 24564

American (AMR) AF: 0.0416 AC: 931 AN: 22396

Ashkenazi Jewish (ASJ) AF: 0.0396 AC: 816 AN: 20610

East Asian (EAS) AF: 0.0391 AC: 1188 AN: 30420

South Asian (SAS) AF: 0.0422 AC: 2654 AN: 62864

European-Finnish (FIN) AF: 0.0349 AC: 1209 AN: 34652

Middle Eastern (MID) AF: 0.0259 AC: 115 AN: 4440

European-Non Finnish (NFE) AF: 0.0336 AC: 29695 AN: 882866

Other (OTH) AF: 0.0373 AC: 1766 AN: 47286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00535 AC: 760 AN: 142128 Hom.: 5 Cov.: 31 AF XY: 0.00511 AC XY: 352 AN XY: 68946

African (AFR) AF: 0.0166 AC: 648 AN: 38950

American (AMR) AF: 0.00200 AC: 28 AN: 14016

Ashkenazi Jewish (ASJ) AF: 0.00599 AC: 20 AN: 3338

East Asian (EAS) AF: 0.00142 AC: 7 AN: 4934

South Asian (SAS) AF: 0.000223 AC: 1 AN: 4482

European-Finnish (FIN) AF: 0.00261 AC: 22 AN: 8414

Middle Eastern (MID) AF: 0.00357 AC: 1 AN: 280

European-Non Finnish (NFE) AF: 0.000354 AC: 23 AN: 64924

Other (OTH) AF: 0.00524 AC: 10 AN: 1908

Alfa AF: 0.0123 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.66
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: rs753404083; hg19: chr14-74121531;