chr19-55159118-G-A

Position:

• chr19-55159118-G-A

Variant summary

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

The NM_001256715.2(DNAAF3):​c.1570C>T​(p.Pro524Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,628 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAAF3 NM_001256715.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.459

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061628044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF3	NM_001256715.2	c.1570C>T	p.Pro524Ser	missense_variant	12/12	ENST00000524407.7	NP_001243644.1
DNAAF3	NM_001256714.1	c.1771C>T	p.Pro591Ser	missense_variant	12/12		NP_001243643.1
DNAAF3	NM_178837.4	c.1711C>T	p.Pro571Ser	missense_variant	12/12		NP_849159.2
DNAAF3	NM_001256716.2	c.1408C>T	p.Pro470Ser	missense_variant	12/12		NP_001243645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7	c.1570C>T	p.Pro524Ser	missense_variant	12/12	1	NM_001256715.2	ENSP00000432046	A2
DNAAF3-AS1	ENST00000591665.1	n.180G>A		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460628 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726520

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 16, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.9
DANN	Benign	0.82
DEOGEN2	Benign	0.0039	.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.51	T;T;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N;.;.;N
REVEL	Benign	0.020
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.077	.;B;.;.
Vest4		0.068
MutPred		0.18		.;Gain of relative solvent accessibility (P = 0.005);.;.;
MVP		0.048
MPC		0.38
ClinPred		0.25	T
GERP RS		0.22
Varity_R		0.029
gMVP		0.40

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: rs773825790; hg19: chr19-55670486;