chr14-49633922-A-G

Variant names:

• chr14-49633922-A-G
• rs746189091
• NM_018139.3:c.1228T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018139.3(DNAAF2):​c.1228T>C​(p.Ser410Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,531,272 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S410S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -3.81
• Publications: 0 publications found

Genes affected

DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

DNAAF2 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 10

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056716233).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018139.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	NM_018139.3	MANE Select	c.1228T>C	p.Ser410Pro	missense	Exon 1 of 3	NP_060609.2
	DNAAF2	NM_001083908.2		c.1228T>C	p.Ser410Pro	missense	Exon 1 of 2	NP_001077377.1
	DNAAF2	NM_001378453.1		c.-644T>C		5_prime_UTR	Exon 1 of 2	NP_001365382.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF2	ENST00000298292.13	TSL:1 MANE Select	c.1228T>C	p.Ser410Pro	missense	Exon 1 of 3	ENSP00000298292.8
	DNAAF2	ENST00000406043.3	TSL:1	c.1228T>C	p.Ser410Pro	missense	Exon 1 of 2	ENSP00000384862.3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151586 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000542 AC: 7 AN: 129264 AF XY: 0.0000849

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: 0.000144

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000149 AC: 205 AN: 1379686 Hom.: 0 Cov.: 91 AF XY: 0.000138 AC XY: 94 AN XY: 680382

African (AFR) AF: 0.00 AC: 0 AN: 31426

American (AMR) AF: 0.0000282 AC: 1 AN: 35494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25058

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35648

South Asian (SAS) AF: 0.00 AC: 0 AN: 79026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4622

European-Non Finnish (NFE) AF: 0.000184 AC: 198 AN: 1077186

Other (OTH) AF: 0.0000868 AC: 5 AN: 57602

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151586 Hom.: 0 Cov.: 33 AF XY: 0.0000405 AC XY: 3 AN XY: 74048

African (AFR) AF: 0.00 AC: 0 AN: 41232

American (AMR) AF: 0.00 AC: 0 AN: 15254

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67844

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000480 Hom.: 0

ExAC AF: 0.0000147 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.85
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
PhyloP100		-3.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.010
Sift	Benign	0.18	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.057
MutPred		0.22		Gain of catalytic residue at V412 (P = 0)
MVP		0.10
MPC		0.72
ClinPred		0.055	T
GERP RS		-3.6
Varity_R		0.078
gMVP		0.25
Mutation Taster		=97/3	polymorphism

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: rs746189091; hg19: chr14-50100640; COSMIC: COSV106101259; COSMIC: COSV106101259;