chr19-55159240-A-G

Position:

• chr19-55159240-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001256715.2(DNAAF3):​c.1448T>C​(p.Leu483Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAAF3 NM_001256715.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.51

Genes affected

DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060887486).
• BP6: Variant 19-55159240-A-G is Benign according to our data. Variant chr19-55159240-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1777212.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF3	NM_001256715.2	c.1448T>C	p.Leu483Pro	missense_variant	12/12	ENST00000524407.7	NP_001243644.1
DNAAF3	NM_001256714.1	c.1649T>C	p.Leu550Pro	missense_variant	12/12		NP_001243643.1
DNAAF3	NM_178837.4	c.1589T>C	p.Leu530Pro	missense_variant	12/12		NP_849159.2
DNAAF3	NM_001256716.2	c.1286T>C	p.Leu429Pro	missense_variant	12/12		NP_001243645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7	c.1448T>C	p.Leu483Pro	missense_variant	12/12	1	NM_001256715.2	ENSP00000432046	A2
DNAAF3-AS1	ENST00000591665.1	n.302A>G		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.0
DANN	Benign	0.78
DEOGEN2	Benign	0.0012	.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.40	T;T;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.63	.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.47	N;.;.;N
REVEL	Benign	0.097
Sift	Benign	0.22	T;.;.;T
Sift4G	Uncertain	0.038	D;D;D;D
Polyphen		0.0020	.;B;.;.
Vest4		0.091
MutPred		0.13		.;Gain of relative solvent accessibility (P = 0.0166);.;.;
MVP		0.13
MPC		0.38
ClinPred		0.060	T
GERP RS		-0.12
Varity_R		0.38
gMVP		0.35

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: rs1360301530; hg19: chr19-55670608;