rs761851970

Variant names:

• chr16-84155702-C-G
• rs761851970
• NM_178452.6:c.694C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Moderate PP5_Moderate

The NM_178452.6(DNAAF1):​c.694C>G​(p.Leu232Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.27
• 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: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-84155702-C-G is Pathogenic according to our data. Variant chr16-84155702-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 579235.Status of the report is criteria_provided_single_submitter, 1 stars.

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.694C>G	p.Leu232Val	missense	Exon 5 of 12	NP_848547.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	ENST00000378553.10	TSL:1 MANE Select	c.694C>G	p.Leu232Val	missense	Exon 5 of 12	ENSP00000367815.5
	DNAAF1	ENST00000567918.5	TSL:1	n.694C>G		non_coding_transcript_exon	Exon 5 of 7	ENSP00000455154.1
	DNAAF1	ENST00000963697.1		c.694C>G	p.Leu232Val	missense	Exon 5 of 13	ENSP00000633756.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251486 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

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	Uncertain	0.35
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.015	D
Polyphen		0.98	D
Vest4		0.70
MutPred		0.61		Gain of methylation at K231 (P = 0.0453)
MVP		0.40
MPC		0.12
ClinPred		0.57	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.51
Mutation Taster		=85/15	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: -1
DS_DL_spliceai		0.92		Position offset: 47

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

Other links and lift over

dbSNP: rs761851970; hg19: chr16-84189307;