14-73654842-TA-T

Variant names:

• chr14-73654842-TA-T
• rs1891178211
• NM_031427.4:c.4-2delA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_Moderate PM2 BP6

The NM_031427.4(DNAL1):​c.4-2delA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000778 in 1,336,952 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: DNAL1 NM_031427.4 splice_acceptor, intron
• Clinical Significance: Likely benign no assertion criteria provided 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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06806283 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.3, offset of 0 (no position change), new splice context is: ttcttttttttttttttaAGgcg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 14-73654842-TA-T is Benign according to our data. Variant chr14-73654842-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 3353166.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAL1	NM_031427.4	c.4-2delA		splice_acceptor_variant, intron_variant	Intron 1 of 7	ENST00000553645.7	NP_113615.2
DNAL1	NM_001201366.2	c.-114-2delA		splice_acceptor_variant, intron_variant	Intron 2 of 8		NP_001188295.1
DNAL1	XM_017021679.3	c.-114-2delA		splice_acceptor_variant, intron_variant	Intron 2 of 8		XP_016877168.1
DNAL1	XM_024449715.2	c.-114-2delA		splice_acceptor_variant, intron_variant	Intron 2 of 8		XP_024305483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAL1	ENST00000553645.7	c.4-4delA		splice_region_variant, intron_variant	Intron 1 of 7	1	NM_031427.4	ENSP00000452037.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000778 AC: 104 AN: 1336952 Hom.: 0 Cov.: 33 AF XY: 0.0000683 AC XY: 45 AN XY: 658654

Gnomad4 AFR exome AF: 0.0000707

Gnomad4 AMR exome AF: 0.000123

Gnomad4 ASJ exome AF: 0.0000867

Gnomad4 EAS exome AF: 0.000232

Gnomad4 SAS exome AF: 0.000144

Gnomad4 FIN exome AF: 0.000118

Gnomad4 NFE exome AF: 0.0000635

Gnomad4 OTH exome AF: 0.000127

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

DNAL1-related disorder Benign:1

Apr 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1891178211; hg19: chr14-74121545;