chr16-84159682-T-C

Variant names:

• chr16-84159682-T-C
• rs1555522543
• NM_178452.6:c.749T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178452.6(DNAAF1):​c.749T>C​(p.Leu250Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L250L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

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.749T>C	p.Leu250Pro	missense	Exon 6 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.-8T>C		5_prime_UTR	Exon 2 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.749T>C	p.Leu250Pro	missense	Exon 6 of 12	ENSP00000367815.5	Q8NEP3-1
	DNAAF1	ENST00000567918.5	TSL:1	n.*68T>C		non_coding_transcript_exon	Exon 7 of 7	ENSP00000455154.1	H3BP51
	DNAAF1	ENST00000567918.5	TSL:1	n.*68T>C		3_prime_UTR	Exon 7 of 7	ENSP00000455154.1	H3BP51

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.77		Gain of disorder (P = 0.049)
MVP		0.89
MPC		0.19
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.95
Mutation Taster		=27/73	disease causing

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: rs1555522543; hg19: chr16-84193287;