NM_031427.4:c.4-4A>T

Variant names:

• chr14-73654843-A-T
• rs576147534
• NM_031427.4:c.4-4A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_031427.4(DNAL1):​c.4-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,188,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAL1 NM_031427.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003782
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0200
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-73654843-A-T is Benign according to our data. Variant chr14-73654843-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 414000.Status of the report is criteria_provided_single_submitter, 1 stars.

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.4-4A>T		splice_region intron	N/A	NP_113615.2	Q4LDG9-1
	DNAL1	NM_001201366.2		c.-114-4A>T		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.4-4A>T		splice_region intron	N/A	ENSP00000452037.1	Q4LDG9-1
	DNAL1	ENST00000554871.5	TSL:1	c.-114-4A>T		splice_region intron	N/A	ENSP00000451834.1	Q4LDG9-3
	DNAL1	ENST00000893991.1		c.4-4A>T		splice_region intron	N/A	ENSP00000564050.1

Frequencies

GnomAD3 genomes AF: 0.0000202 AC: 3 AN: 148814 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00367 AC: 338 AN: 92032 AF XY: 0.00362

Gnomad AFR exome AF: 0.00300

Gnomad AMR exome AF: 0.00963

Gnomad ASJ exome AF: 0.00177

Gnomad EAS exome AF: 0.00598

Gnomad FIN exome AF: 0.00261

Gnomad NFE exome AF: 0.00260

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00132 AC: 1574 AN: 1188308 Hom.: 0 Cov.: 33 AF XY: 0.00139 AC XY: 811 AN XY: 582942

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

African (AFR) AF: 0.00175 AC: 43 AN: 24514

American (AMR) AF: 0.00616 AC: 115 AN: 18670

Ashkenazi Jewish (ASJ) AF: 0.00250 AC: 48 AN: 19176

East Asian (EAS) AF: 0.00321 AC: 89 AN: 27694

South Asian (SAS) AF: 0.00362 AC: 205 AN: 56618

European-Finnish (FIN) AF: 0.00259 AC: 90 AN: 34712

Middle Eastern (MID) AF: 0.00128 AC: 6 AN: 4686

European-Non Finnish (NFE) AF: 0.000934 AC: 891 AN: 954370

Other (OTH) AF: 0.00182 AC: 87 AN: 47868

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0000201 AC: 3 AN: 148908 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 1 AN XY: 72566

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

African (AFR) AF: 0.0000247 AC: 1 AN: 40514

American (AMR) AF: 0.000133 AC: 2 AN: 15034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67330

Other (OTH) AF: 0.00 AC: 0 AN: 2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00380082), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00436 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Primary ciliary dyskinesia 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.45
DANN	Benign	0.66
PhyloP100		0.020
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs576147534; hg19: chr14-74121546; COSMIC: COSV60726634; COSMIC: COSV60726634;