rs145075337

Variant names:

• chr16-84176072-C-A
• rs145075337
• NM_178452.6:c.1838C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-84176072-C-A
• chr16-84176072-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_178452.6(DNAAF1):​c.1838C>A​(p.Thr613Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.205
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09550765).

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.1838C>A	p.Thr613Asn	missense	Exon 11 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.1130C>A	p.Thr377Asn	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.1838C>A	p.Thr613Asn	missense	Exon 11 of 12	ENSP00000367815.5	Q8NEP3-1
	DNAAF1	ENST00000963697.1		c.1844C>A	p.Thr615Asn	missense	Exon 11 of 13	ENSP00000633756.1
	DNAAF1	ENST00000963694.1		c.1838C>A	p.Thr613Asn	missense	Exon 11 of 13	ENSP00000633753.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251190 AF XY: 0.000199

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000266 AC: 389 AN: 1461836 Hom.: 0 Cov.: 56 AF XY: 0.000270 AC XY: 196 AN XY: 727210

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

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

European-Non Finnish (NFE) AF: 0.000337 AC: 375 AN: 1111988

Other (OTH) AF: 0.000199 AC: 12 AN: 60392

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74308

African (AFR) AF: 0.000121 AC: 5 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000351 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia 13 (2)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.20
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.037
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.071
MVP		0.50
MPC		0.022
ClinPred		0.038	T
GERP RS		3.7
PromoterAI		0.019	Neutral
Varity_R		0.13
gMVP		0.15
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs145075337; hg19: chr16-84209678;