14-73654828-CTTTTTTTTT-CTTTTTTTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_031427.4(DNAL1):​c.4-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 141,702 control chromosomes in the GnomAD database, including 42 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (42 hom., cov: 31)
  • Exomes 𝑓: 0.34 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAL1 NM_031427.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 14-73654828-CT-C is Benign according to our data. Variant chr14-73654828-CT-C is described in ClinVar as Benign. ClinVar VariationId is 1295016.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0171 (2424/141702) while in subpopulation AFR AF = 0.0415 (1616/38902). AF 95% confidence interval is 0.0399. There are 42 homozygotes in GnomAd4. There are 1170 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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.4-5delT		splice_region intron	N/A	NP_113615.2	Q4LDG9-1
	DNAL1	NM_001201366.2		c.-114-5delT		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.4-18delT		intron	N/A	ENSP00000452037.1	Q4LDG9-1
	DNAL1	ENST00000554871.5	TSL:1	c.-114-18delT		intron	N/A	ENSP00000451834.1	Q4LDG9-3
	DNAL1	ENST00000893991.1		c.4-18delT		intron	N/A	ENSP00000564050.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2417 AN: 141688 Hom.: 41 Cov.: 31

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.0193

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00661

Gnomad EAS AF: 0.00141

Gnomad SAS AF: 0.000445

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00993

Gnomad NFE AF: 0.00682

Gnomad OTH AF: 0.0133

GnomAD2 exomes AF: 0.401 AC: 29770 AN: 74314 AF XY: 0.414

Gnomad AFR exome AF: 0.361

Gnomad AMR exome AF: 0.410

Gnomad ASJ exome AF: 0.434

Gnomad EAS exome AF: 0.409

Gnomad FIN exome AF: 0.353

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.409

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.338 AC: 292317 AN: 863578 Hom.: 2 Cov.: 0 AF XY: 0.340 AC XY: 145929 AN XY: 429308

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

African (AFR) AF: 0.342 AC: 6731 AN: 19708

American (AMR) AF: 0.341 AC: 6731 AN: 19714

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 5983 AN: 16948

East Asian (EAS) AF: 0.354 AC: 8697 AN: 24552

South Asian (SAS) AF: 0.347 AC: 18528 AN: 53446

European-Finnish (FIN) AF: 0.323 AC: 9591 AN: 29696

Middle Eastern (MID) AF: 0.249 AC: 925 AN: 3716

European-Non Finnish (NFE) AF: 0.338 AC: 222345 AN: 658542

Other (OTH) AF: 0.343 AC: 12786 AN: 37256

⚠️ 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: 0.0171 AC: 2424 AN: 141702 Hom.: 42 Cov.: 31 AF XY: 0.0170 AC XY: 1170 AN XY: 68694

African (AFR) AF: 0.0415 AC: 1616 AN: 38902

American (AMR) AF: 0.0103 AC: 144 AN: 13990

Ashkenazi Jewish (ASJ) AF: 0.00661 AC: 22 AN: 3330

East Asian (EAS) AF: 0.00142 AC: 7 AN: 4928

South Asian (SAS) AF: 0.000447 AC: 2 AN: 4478

European-Finnish (FIN) AF: 0.0176 AC: 147 AN: 8372

Middle Eastern (MID) AF: 0.0108 AC: 3 AN: 278

European-Non Finnish (NFE) AF: 0.00682 AC: 441 AN: 64644

Other (OTH) AF: 0.0132 AC: 25 AN: 1898

Alfa AF: 0.0877 Hom.: 6

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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; COSMIC: COSV60729191; COSMIC: COSV60729191;