16-84170178-G-A

Variant names:

• chr16-84170178-G-A
• rs148990251
• NM_178452.6:c.1350G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_178452.6(DNAAF1):​c.1350G>A​(p.Pro450Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,611,788 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: DNAAF1 NM_178452.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.57
• 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=-0.91).
• BP6: Variant 16-84170178-G-A is Benign according to our data. Variant chr16-84170178-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242157.
• BP7: Synonymous conserved (PhyloP=-1.58 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000165 (241/1460106) while in subpopulation MID AF = 0.000697 (4/5736). AF 95% confidence interval is 0.000371. There are 0 homozygotes in GnomAdExome4. There are 125 alleles in the male GnomAdExome4 subpopulation. Median coverage is 94. This position passed quality control check.

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.1350G>A	p.Pro450Pro	synonymous	Exon 8 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.642G>A	p.Pro214Pro	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.1350G>A	p.Pro450Pro	synonymous	Exon 8 of 12	ENSP00000367815.5	Q8NEP3-1
	DNAAF1	ENST00000963697.1		c.1350G>A	p.Pro450Pro	synonymous	Exon 8 of 13	ENSP00000633756.1
	DNAAF1	ENST00000963694.1		c.1350G>A	p.Pro450Pro	synonymous	Exon 8 of 13	ENSP00000633753.1

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 37 AN: 151568 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000329

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: 0.000162

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 250870 AF XY: 0.000140

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000165 AC: 241 AN: 1460106 Hom.: 0 Cov.: 94 AF XY: 0.000172 AC XY: 125 AN XY: 726404

African (AFR) AF: 0.000568 AC: 19 AN: 33444

American (AMR) AF: 0.000158 AC: 7 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86176

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.000697 AC: 4 AN: 5736

European-Non Finnish (NFE) AF: 0.000167 AC: 185 AN: 1110852

Other (OTH) AF: 0.000332 AC: 20 AN: 60304

GnomAD4 genome AF: 0.000244 AC: 37 AN: 151682 Hom.: 0 Cov.: 32 AF XY: 0.000270 AC XY: 20 AN XY: 74156

African (AFR) AF: 0.000484 AC: 20 AN: 41282

American (AMR) AF: 0.000328 AC: 5 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67882

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000204 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.4
DANN	Benign	0.44
PhyloP100		-1.6

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: rs148990251; hg19: chr16-84203784; COSMIC: COSV100533708; COSMIC: COSV100533708;