16-84145313-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_178452.6(DNAAF1):c.-128G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,486,218 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 32)
  • Exomes 𝑓: 0.017 (237 hom.)
• Consequence: DNAAF1 NM_178452.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.639

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0139 (2122/152252) while in subpopulation NFE AF= 0.0198 (1348/67996). AF 95% confidence interval is 0.0189. There are 24 homozygotes in gnomad4. There are 1036 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.-128G>C		5_prime_UTR_variant	1/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.-128G>C		5_prime_UTR_variant	1/12	1	NM_178452.6	P1
DNAAF1	ENST00000567918.5	c.-128G>C		5_prime_UTR_variant, NMD_transcript_variant	1/7	1
DNAAF1	ENST00000570298.5	n.27G>C		non_coding_transcript_exon_variant	1/11	2
DNAAF1	ENST00000563093.5	c.-128G>C		5_prime_UTR_variant, NMD_transcript_variant	1/11	2

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2123 AN: 152134 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0170 AC: 22652 AN: 1333966 Hom.: 237 Cov.: 22 AF XY: 0.0166 AC XY: 10964 AN XY: 658696

Gnomad4 AFR exome AF: 0.00318

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00423

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0191

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0139 AC: 2122 AN: 152252 Hom.: 24 Cov.: 32 AF XY: 0.0139 AC XY: 1036 AN XY: 74462

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0223

Gnomad4 NFE AF: 0.0198

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0180 Hom.: 4

Bravo AF: 0.0125

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia 13 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	3.1
Dann	Benign	0.36

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140245131; hg19: chr16-84178918;