rs760933549

Positions:

• chr14-49634021-C-G
• chr14-49634021-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018139.3(DNAAF2):​c.1129G>C​(p.Gly377Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,522,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G377V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.398

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023260891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF2	NM_018139.3	c.1129G>C	p.Gly377Arg	missense_variant	1/3	ENST00000298292.13
DNAAF2	NM_001083908.2	c.1129G>C	p.Gly377Arg	missense_variant	1/2
DNAAF2	NM_001378453.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13	c.1129G>C	p.Gly377Arg	missense_variant	1/3	1	NM_018139.3	P2
DNAAF2	ENST00000406043.3	c.1129G>C	p.Gly377Arg	missense_variant	1/2	1		A2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000130 AC: 15 AN: 115020 Hom.: 0 AF XY: 0.000158 AC XY: 10 AN XY: 63162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000292 AC: 400 AN: 1370448 Hom.: 0 Cov.: 89 AF XY: 0.000308 AC XY: 208 AN XY: 675622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000597

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000277

Gnomad4 NFE exome AF: 0.000350

Gnomad4 OTH exome AF: 0.000175

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24 AN XY: 74344

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000276

ExAC AF: 0.0000417 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 11, 2021	The c.1129G>C (p.G377R) alteration is located in exon 1 (coding exon 1) of the DNAAF2 gene. This alteration results from a G to C substitution at nucleotide position 1129, causing the glycine (G) at amino acid position 377 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 11, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 377 of the DNAAF2 protein (p.Gly377Arg). This variant is present in population databases (rs760933549, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DNAAF2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411170). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 28, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 23, 2023	BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.0053	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.023	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.015
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.048	D;D
Polyphen		0.048	B;B
Vest4		0.12
MVP		0.17
MPC		1.1
ClinPred		0.18	T
GERP RS		-1.5
Varity_R		0.089
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs760933549; hg19: chr14-50100739;