16-84175892-T-C

Variant names:

• chr16-84175892-T-C
• rs4782899
• NM_178452.6:c.1699-41T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178452.6(DNAAF1):​c.1699-41T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,608,462 control chromosomes in the GnomAD database, including 99,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7320 hom., cov: 33)
  • Exomes 𝑓: 0.35 (92368 hom.)
• Consequence: DNAAF1 NM_178452.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.566
• Publications: 14 publications found

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]

DNAAF1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-84175892-T-C is Benign according to our data. Variant chr16-84175892-T-C is described in ClinVar as Benign. ClinVar VariationId is 262944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF1	NM_178452.6	c.1699-41T>C		intron_variant	Intron 10 of 11	ENST00000378553.10	NP_848547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1699-41T>C		intron_variant	Intron 10 of 11	1	NM_178452.6	ENSP00000367815.5

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43732 AN: 152016 Hom.: 7306 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.295

GnomAD2 exomes AF: 0.345 AC: 85630 AN: 248470 AF XY: 0.343

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.376

Gnomad FIN exome AF: 0.359

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.352 AC: 512111 AN: 1456330 Hom.: 92368 Cov.: 32 AF XY: 0.349 AC XY: 252637 AN XY: 724750

African (AFR) AF: 0.0967 AC: 3233 AN: 33450

American (AMR) AF: 0.463 AC: 20723 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7754 AN: 26112

East Asian (EAS) AF: 0.378 AC: 14981 AN: 39680

South Asian (SAS) AF: 0.269 AC: 23153 AN: 86122

European-Finnish (FIN) AF: 0.360 AC: 18144 AN: 50424

Middle Eastern (MID) AF: 0.273 AC: 1572 AN: 5762

European-Non Finnish (NFE) AF: 0.363 AC: 402677 AN: 1109766

Other (OTH) AF: 0.330 AC: 19874 AN: 60300

GnomAD4 genome AF: 0.288 AC: 43754 AN: 152132 Hom.: 7320 Cov.: 33 AF XY: 0.292 AC XY: 21674 AN XY: 74350

African (AFR) AF: 0.108 AC: 4492 AN: 41522

American (AMR) AF: 0.390 AC: 5950 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1050 AN: 3470

East Asian (EAS) AF: 0.372 AC: 1920 AN: 5160

South Asian (SAS) AF: 0.272 AC: 1312 AN: 4822

European-Finnish (FIN) AF: 0.366 AC: 3873 AN: 10590

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24059 AN: 67980

Other (OTH) AF: 0.292 AC: 617 AN: 2114

Alfa AF: 0.303 Hom.: 1399

Bravo AF: 0.287

Asia WGS AF: 0.283 AC: 984 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.62
PhyloP100		-0.57
PromoterAI		0.17	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs4782899; hg19: chr16-84209498; COSMIC: COSV58988077; COSMIC: COSV58988077;