14-73654843-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_031427.4(DNAL1):c.4-4A>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003782
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0200

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 414000.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAL1	NM_031427.4	c.4-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000553645.7
DNAL1	NM_001201366.2	c.-114-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DNAL1	XM_017021679.3	c.-114-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DNAL1	XM_024449715.2	c.-114-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAL1	ENST00000553645.7	c.4-4A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_031427.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3 AN: 148814 Hom.: 0 Cov.: 31 FAILED QC

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

GnomAD3 exomes AF: 0.00367 AC: 338 AN: 92032 Hom.: 0 AF XY: 0.00362 AC XY: 180 AN XY: 49670

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 SAS exome AF: 0.00313

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

Gnomad4 AFR exome AF: 0.00175

Gnomad4 AMR exome AF: 0.00616

Gnomad4 ASJ exome AF: 0.00250

Gnomad4 EAS exome AF: 0.00321

Gnomad4 SAS exome AF: 0.00362

Gnomad4 FIN exome AF: 0.00259

Gnomad4 NFE exome AF: 0.000934

Gnomad4 OTH exome AF: 0.00182

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

Gnomad4 AFR AF: 0.0000247

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00436 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 16 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.45
Dann	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs576147534; hg19: chr14-74121546; COSMIC: COSV60726634; COSMIC: COSV60726634;