16-84170127-C-T

Variant names:

• chr16-84170127-C-T
• rs141074491
• NM_178452.6:c.1299C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_178452.6(DNAAF1):​c.1299C>T​(p.Asp433Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,569,810 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (3 hom.)
• Consequence: DNAAF1 NM_178452.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.66
• Publications: 1 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: ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-84170127-C-T is Benign according to our data. Variant chr16-84170127-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 262939.
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178452.6. 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
	DNAAF1	NM_178452.6	MANE Select	c.1299C>T	p.Asp433Asp	synonymous	Exon 8 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.591C>T	p.Asp197Asp	synonymous	Exon 4 of 8	NP_001305685.1	Q8NEP3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	ENST00000378553.10	TSL:1 MANE Select	c.1299C>T	p.Asp433Asp	synonymous	Exon 8 of 12	ENSP00000367815.5	Q8NEP3-1
	DNAAF1	ENST00000963697.1		c.1299C>T	p.Asp433Asp	synonymous	Exon 8 of 13	ENSP00000633756.1
	DNAAF1	ENST00000963694.1		c.1299C>T	p.Asp433Asp	synonymous	Exon 8 of 13	ENSP00000633753.1

Frequencies

GnomAD3 genomes AF: 0.000450 AC: 63 AN: 140010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000500

Gnomad ASJ AF: 0.00681

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000686

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000170

Gnomad OTH AF: 0.00207

GnomAD2 exomes AF: 0.000490 AC: 123 AN: 251192 AF XY: 0.000457

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000294 AC: 420 AN: 1429690 Hom.: 3 Cov.: 96 AF XY: 0.000288 AC XY: 205 AN XY: 710662

African (AFR) AF: 0.000397 AC: 13 AN: 32750

American (AMR) AF: 0.000392 AC: 17 AN: 43386

Ashkenazi Jewish (ASJ) AF: 0.00845 AC: 210 AN: 24848

East Asian (EAS) AF: 0.00 AC: 0 AN: 36754

South Asian (SAS) AF: 0.000204 AC: 17 AN: 83196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52814

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5464

European-Non Finnish (NFE) AF: 0.000115 AC: 126 AN: 1091988

Other (OTH) AF: 0.000615 AC: 36 AN: 58490

GnomAD4 genome AF: 0.000450 AC: 63 AN: 140120 Hom.: 0 Cov.: 32 AF XY: 0.000469 AC XY: 32 AN XY: 68182

African (AFR) AF: 0.000407 AC: 15 AN: 36880

American (AMR) AF: 0.000499 AC: 7 AN: 14024

Ashkenazi Jewish (ASJ) AF: 0.00681 AC: 23 AN: 3378

East Asian (EAS) AF: 0.00 AC: 0 AN: 4710

South Asian (SAS) AF: 0.000687 AC: 3 AN: 4366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000170 AC: 11 AN: 64798

Other (OTH) AF: 0.00205 AC: 4 AN: 1950

Alfa AF: 0.000848 Hom.: 0

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not specified (1)
-	1	-	Primary ciliary dyskinesia 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.25
DANN	Benign	0.14
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

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: rs141074491; hg19: chr16-84203733; COSMIC: COSV100533617;