rs727502965

Positions:

• chr14-49625844-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PVS1 PM2 BP6_Moderate

The NM_001378453.1(DNAAF2):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000288 in 1,457,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: DNAAF2 NM_001378453.1 start_lost
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.232

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 14-49625844-T-C is Benign according to our data. Variant chr14-49625844-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 163092.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF2	NM_018139.3	c.2212A>G	p.Met738Val	missense_variant	3/3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001378453.1	c.1A>G	p.Met1?	start_lost	2/2		NP_001365382.1
DNAAF2	NM_001083908.2	c.2068A>G	p.Met690Val	missense_variant	2/2		NP_001077377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13	c.2212A>G	p.Met738Val	missense_variant	3/3	1	NM_018139.3	ENSP00000298292.8
DNAAF2	ENST00000406043.3	c.2068A>G	p.Met690Val	missense_variant	2/2	1		ENSP00000384862.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1457660 Hom.: 0 Cov.: 33 AF XY: 0.0000276 AC XY: 20 AN XY: 724818

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 01, 2014

Met738Val in exon 3 of DNAAF2: This variant is not expected to have clinical sig nificance due to a lack of evolutionary conservation of the affected amino acid. Of note, >10 mammalian species have a valine (Val) at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.81
DEOGEN2	Benign	0.0053	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.024
Sift	Benign	0.82	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.0	B;B
Vest4		0.012
MutPred		0.22		Gain of sheet (P = 0.0085);.;
MVP		0.20
MPC		0.52
ClinPred		0.039	T
GERP RS		0.90
Varity_R		0.020
gMVP		0.053

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727502965; hg19: chr14-50092562;