16-84176050-A-C

Variant names:

• chr16-84176050-A-C
• rs146607878
• NM_178452.6:c.1816A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178452.6(DNAAF1):​c.1816A>C​(p.Ile606Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I606V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1816A>C	p.Ile606Leu	missense	Exon 11 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.1108A>C	p.Ile370Leu	missense	Exon 7 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.1816A>C	p.Ile606Leu	missense	Exon 11 of 12	ENSP00000367815.5	Q8NEP3-1
	DNAAF1	ENST00000963697.1		c.1822A>C	p.Ile608Leu	missense	Exon 11 of 13	ENSP00000633756.1
	DNAAF1	ENST00000963694.1		c.1816A>C	p.Ile606Leu	missense	Exon 11 of 13	ENSP00000633753.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0043	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.25	T
Polyphen		0.94	P
Vest4		0.45
MutPred		0.22		Gain of catalytic residue at I606 (P = 0.0446)
MVP		0.37
MPC		0.16
ClinPred		0.91	D
GERP RS		4.9
PromoterAI		0.083	Neutral
Varity_R		0.31
gMVP		0.080
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 10

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

Other links and lift over

dbSNP: rs146607878; hg19: chr16-84209656;